.

2004


, . (
5343/32, . 202 2)

.
.

.......
..






.

,
.
.
,
. ,

.
,
.
.
.
,
.

.

. , . .

, .
,
R .
,
.
,

. .

1
.

12

12

(EGFR)
HER2
(VEGF)
Ras/MAPK
Ras
(PDGF)
Bcr-Abl

(FGFR )

15
15
19
24
27
31
34
40
41
44

(Resident nuclear proteins)

AP-1 (Jun-Fos)

JAK/STATs
NF-B
WNT-

63
63
65
67
69
72
72
74
78

82

CDKs
CDKs
CDKs

&

82
83
85
86
88
90
92
93
95

108

CDKs

CDKs
CDKs (CKIs)
CDKs: pRb
pRb
: p53
p53
p53
p53

108
108
109
110
111
113
114
116
120
122

129

CDKs
CDKs
ATP CDKs
ATP-

(butyrolactone)
[2,3-a]

[2,3-d]

Paullones
Fascaplysin
Hymenialdsisine

130
132
133
135
135
138
143
144
146
148
150
153
156
157

ii

159
160

173

DNA I


topo I
topo I
topo I
topo I .

174
175
176
178
180
181
181
183
185
187
188

196

topo I
(CPTs)


CPT
- CPTs

, .

Rebeccamycin

rebeccamycin
rebeccamycin
topo I
Tjipanazoles
Arcyriaflavins
5,11-dihydroindolo[3,2-b]carbazoles
5,6,11,12-[2,3-a]

topo I

196
196
197
198
200
201
208
209
210
211
212

iii

215
222
230
230
233
235
237
237
237

DNA
Bulgarein
DNA .
-
topo I

238
238
238
238
239

259

263

263
265
266

10


2--
2- 2,4-

Friedel-Crafts 2--

267
267

270
271
277

11

285

Fischer
Fischer
Fischer

285
288
289
291
293
294

iv

[2,3-a]

[2,3-a]

PPSE
[2,3-a]



[2,3-a]
Fischer 3--7--4,5,6,7 (37)

296
297
302
303
305
309
311

313

12

4-(2-4-) (30)
Beckmann 4-(3)-2-
(113)

Fischer 4-[2-(1,3)]-7--4,5,6,7--
(40)
1,3- 4[2-(1,3-)]-7--4,5,6,7- (40)

323

323
324

326
328

329

330

13




2-- (2)

4-[2-(1,3-)]-4-(2--4-) (39)

333
333
335
337
338

(diethoxymethyl, DEM)

339
341
344

14

-
DEM-
-

348
348
348
353
355

15


- (128)

(141)
- (128)
-- (129)
- (127)
127 3-




(127)

(127)
4,7-
Pd-

358
358
359
363
366
369
371
371
371
373
374
377
378
381
382

393

vi

16

395

395

2- (2)
2-- (13)
2-- (2)
7--4,5,6,7--2 (34)
4--4-(2--4-)
(30)
4-(2--4-) (32)
7--4,5,6,7--2-
(34)
4-(3-)-2 (31)
4-(3-)-2 (33)
4-(2--4-) (32)
4--4-(2-4-)
4-(3-)-2 (31)
4-(3-)-2 (35)
6--7--4,5,6,7--2 (36)
3--7--4,5,6,7--2 (37)

3--7--4,5,6,7--2 (37)
4-[2-(1,3-)]-7--4,5,6,7--2- (40)
4-[2-(1,3-)]-4-(2--4-)
(38)
A 4-[2-(1,3-)]-7--4,5,6,7-2- (40)
4-[2-(1,3-)]4-(2--4-)
4-[2-(1,3-)]-4-(2-4-) (39)

vii

395
395
395
396
396
397
397
398
399
399
400
400
401
401
402
402
402
403
403
404
405
405

[2,3-a]

[2,3-a]
(105a-i)
PPSE
(80a-i)
4,5--[2,3-a]
(106a-i)
3--[2,3-a]

(108a-i)
PPSE
(107a-i)
3--4,5--[2,3a] 109(a-i)

406
406
406
406
406
407
410
410
410
410
410

413

4-(2-4-) (30)
syn- 4-(3) -2-
(112)
syn- 4-(3) -2-
(113)
4-[2-(1,3)]-7--4,5,6,7--2-
(114a 114b)

417

419

--
1--2- (120)
1--4-(3 )-2-
(132)
4-[2-(1,3-)]-4-(1-2--4-

viii

413

415

416

419
419

420
421

) (121)
4-[2-(1,3-)]-4-(1-2---4) (133)
1--4-[2-(1,3)]-7--4,5,6,7--2 (134)
--
1--2- (123)
1--4-[2-(1,3)]-4-(2--4) (124)
--
-


4-[2-(1,3-)]-4-(1--2-4-) (137)
(137) 1--4[2-(1,3-)]-7--4,5,6,7--2 (128)
-

anti- 1--4-[2-(1,3)]-7--4,5,6,7--2-
(140)
Beckmann 1--4[2-(1,3-)]-7--4,5,6,7--2
1,3- 1-4-[2-(1,3-)]-7--4,5,6,7--2
syn- 1--4-(3)-2-
(147)
1--3--7--4,5,6,7-2- (151)
1--3--7--4,5,6,7-2- (153)
1--7--4,5,6,7,8-[2,3-b]-2- (154)

ix

422

422
423
423

424
424

424
426

427

428

428

429

430

430
431
432
433

8--1--7--4,5,6,7,8-[2,3-b]-2- (155)

433

[3,2b]

435

1--7--4,5,6,7-2- (127)
1--4, 7-4,7--2- (146)
1--4, 7--5(N-)-4,7--2- (160)

435
436
437

[2,3-a]
C6

[2,3-a]
DNA-
[2,3-a]
-
1 (CDK1)
In vivo [2,3-a]

451
451
452

457

475

SUMMARY

483

441

443
447

449

1. FLV-3
.
2. [2,3-d] .
3. (M)
paullones.
4. DNA .
5. J-107088
Xenografts PC-3
.
6. Friedel-Crafts 2 Lewis.
7. Friedel-Crafts 2
AlCl3.
8. 2
.
9. Friedel-Crafts 26 Lewis.
10.
[2,3-a]
.
11. PPSE .
12. [2,3-a] .
13. 3--[2,3-a]
.
14. - 30.
15. Beckmann 113.
16. 40.
17. 34
.
18. 39
.
19.
.
20.
39.

xi

21. Friedel-Crafts 120

.
22. Friedel-Crafts 120
3- .
23. 140.
24. Beckmann 140.
25. 1,3-
141.
26. 1,3-
128.
27. 127.
28. [2,3-a]
.
29. [2,3-a]
.
30. 3-[2,3-a] .
31. 3--[2,3a] .

xii

abs.

absolute

Ah

Aryl hydrocarbon

AMP

Adenosine monophosphate

Ar

aromatic

Arg

Asp

ATP

Adenosine 5-triphosphate

CAKs

CDK activating kinases

CAM

Chorioallantoic membrane

CAN

CDKs

Cyclin dependent kinases

CKIs

CDK inhibitors

CPT

doublet

DCM

DDQ

2,3-dichloro-5,6-dicyano-1,4-benzoquinone

DEM

diethoxymethyl

DMF

DMP

Dess-Martin periodinate

DMSO

DNA

dsb

double strand breaks

EGF

Epidermal growth factor

ERKs

Extracellular signal-regulated kinases

FGF

Fibroplast growth factor

FTIs

Farnesyltransferse inhibitors

GBM

GDP

Guanosine diphosphate

Glu

GSK

Glygogen synthase kinase

GTP

Guanosine triphosphate

hour

HCMV

Human cytomegalovirus

His

HMDS

Hexamethyldisiloxane

HPLC

IBX

o-iodoxybenzoic acid

IC50

50% inhibitory concentration

IL-1

I 1

IR

xiii

Leu

Lys

multiplet

MAPK

Mitogen-activated protein kinase

NF-B

Nuclear factor B

NMR

PCC

PDGF

Platelet-derived growth factor

PKC

Protein kinase C

PPA

PPSE

Polyphosphoric acid trimethylsilyl ester

pRb

Retinoblastoma protein

p-TsOH

quartet

Reflux

RTKs

Receptor tyrosine kinases

singlet

Ser

Serine

ssb

single-strand break

STATs

Signal transducers and activators of transcription

triplet

TBAB

TBHP

TCDD

2,3,7,8-tetrachlorodibenzo-p-dioxin

TFA

THF

Thr

TLC

TNF-

Tumor necrosis factor-

topo

VEGF

Vascular endothelial growth factor

Wat

..

xiv

,
,
.
,

.

,

, ,
,
, ,

1 .

, .

, ,


,
. ,


,
/

3 .

-3-

4 ,

, (antisense
oligonucleotides), ,

.
:
.
5 , (WHO)
10.000.000 2000

, 15.000.000

2020.

, ,

.

, ,

. ,

6 ,


.


7 ,
,
.

.
,

.

-4-

DNA
.

,

.

,

,
.
2
.

.
,

.
/
, (genetic instability),

(proliferative

signal

transduction), ,
, .
:

. 1990,
10
, .

-5-

600.000.000 ,

10.000

3-5,
. ,
, ,
.

.

, ,
- , ,
8 .
,

9

.

(high-throughput

screening,
(genomics),

-6-

HTS),

(bioinformatics), (profiling gene

expression)
(proteomics)

,
(lead compound).
(screening)
(rational drug design).
, .

10,11 .

(computational

chemistry)

12 . , (combinatorial chemistry)

13 .
National
Cancer Institute

14

.

.

(Structural

Biology),

- (nuclear magnetic
resonance, NMR) 15 .
- (Structure-Activity Relationships, SAR) NMR

. ,
,

, ,
- 16 .

-7-

.

,
-
17 .
,


. ,
,

18 .

Cancer Research Campaign (CRC) European Organization for
Research and Treatment of Cancer (EORTC)
19 .

.
20, 21 , 22 :

[signal transduction pathways,

. RTKs]

[serine/threonine kinases]

, [ ]

, [Bcl-2, MDM2, COX-2, .]

, [MMPs]

, [p53]

, [DNMT, HDACs]

[Hsp90]

, [HIF-1]

, []

, []

-8-

. ,

,

,

,
. ,


.
Gleevec ( Bcr-Abl)
Herceptin ( -ErbB2 ),
.
,
,
, ,
, ,
.
,

.

,
,
.

, -

1 (CDK1), (topo I)

-9-

.
,
,
-

.

Hanahan D., and Weinberg A., The hallmarks of cancer, Cell, 57-70,
100, 2000.

Verweij J. and De Jonge M.J.A., Achievements and future of

chemotherapy, Eur. J. Cancer, 1479, 36, 2000.

Workman P., The potential for molecular oncology to define new

drug targets, In: Kerr D.J., Workman P., (Eds), New Molecular
Targets for Cancer Chemotherapy, CRC Press Inc., Boca Raton,
Florida, 1994, pp. 1-29.

Workman P., Emerging molecular therapies: Small molecule drugs,

In: Bronchud M.H., Foote M., Peters W.P., Robinson M.O., (Eds),
Principles of Molecular Oncology, Humana Press, Totowa, 1999, pp.
413-429.

World Cancer Report, Stewart B.W., Kleihues P., (Eds), International

Agency for Research on Cancer, World Health Organization, 2003.

Rothenberg M.L., Carbone D.P. and Johnson D.H., Improving the

evaluation of new cancer treatments: Challenges and opportunities,
Nat. Rev. Cancer, 303-308, 3, 2003.

Garrett M.D., Workman P., Discovering novel chemotherapeutic

drugs for the thrird millenium, Eur. J. Cancer, 2010-2030, 35, 1999.

Lane D., The promise of molecular oncology, Lancet, 17-20, 351

(Suppl. II), 1998.

Ventor J.C., The sequence of the human genome, Nature, 13041351, 291, 2001.

10

Bevan P., Ryder H., Shaw I., Identifying small-molecule lead

compounds: The screening approach to drug discovery, Trends
Biotechnol., 115-121, 13, 1995.

11

Dove A., Drug screening-beyond the bottleneck, Nat. Biotechnol.,

859-862, 17, 1999.

12

Willet P., Computational Methods for the Analysis of Molecular

Diversity, Perspect. Drug Disc. Design, 1-11, 7/8, 1997.

13

Hogan J.C., Combinatorial chemistry in drug discovery, Nat.

Biotechnol., 328-340, 15, 1997.

-10-

14

Monks A., Scudiero D.A., Johnson G.S., Paull K.D., Sausville E.A.,
The NCI anti-cancer drug screen to identify effectors of novel
targets, Anticancer Drug Des., 533-541, 12, 1997.

15

Kubinyi H., Structure-based design of enzyme inhibitors and

receptor lignads, Curr. Opin. Drug Discovery and Development, 415, 1, 1998.

16

Crews C. M., Splittgerber U., Chemical genetics: exploring and

controlling cellular processes with chemical probes, Trends Biochem.
Sci., 317-320, 24, 1999.

17

King F.D., Medicinal Chemistry: Principles and Practice, Royal Society

of Chemistry, Cambridge, 1994, pp. 179-188.

18

Workman P., Pharmacokinetics and cancer: Successes, failures and

future prospects, In: Workman P., Graham M.A., (Eds),
Pharmacokinetics and Cancer Chemotherapy. Cancer Surveys, Vol.
17, New York, Cold Spring Harbor Laboratory Press, 1993, pp. 1-26.

19

Burtless S.S., Jordrel D.I., Newell D.R., Evaluation of rodent only

preclinical toxicology for phase I trials of new cytotoxic anticancer
agents in Europe, Eur. J. Cancer, 408-410, 31A, 1995.

20

Buolamwini J.K., Novel anticancer drug discovery, Curr. Opin.

Chem. Biol., 500-509, 3, 1999.

21

Novotny L., Szekeres T., Cancer Therapy:

chemotherapy, Hematology, 129-137, 8, 2003.

22

Workman P. Kaye S. B., Translating basic cancer research into new

cancer therapeutics, Trends Mol. Med., S1-S9, 8, 2002.

-11-

New

targets

for

1:

.



.
, ,
.
, .

.
(ligand)
(receptor).

1 :

.
,

()

()

: (channels)
, (transporters)

.

.

-12-

1:

.

.
(signal transduction) 2 .

.


.

(second messenger)
.
.

1. .

-13-

1:

.
.
,

,
-,
.
/-.
G- (G-protein)
. G-

. G-
GDP. ,
G GDP GTP.
G
GTP .
, -,

.
,
AMP (cyclic AMP,
cAMP).

Benjamin Lewin, Genes VII, Oxford University Press, New York, 2000.

Morgan N.G., Cell signaling, Open University Press, Milton Keynes,

UK, 1989.

Hepler J.R., and Gilman A.G., G proteins, Trends Biochem. Sci.,

383-387, 17, 1992.

-14-

2:

,
, , ,
1 . ,
.

(epidermal growth factor, EGF),

(vascular endothelial growth factor, VEGF),
(fibroplast growth factor, FGF)
(platelet-derived growth factor, PDGF) ..

2 .
:
(group I integral membrane proteins),
, -
- .
, EGF PDGF,
, , ,
.

. ,
.

-15-

2:

2. .

ATP ADP.
ATP
3 .

: o -

.

-16-

2:

,
:

-:

-.

50

- .

/-:

/.

: ,

/.
(receptor tyrosine kinases, RTKs) 4 :

.

,
.
,
.

(cascade)

.
.


.

5 .
,

-17-

2:

-.

( , positive feedback)

-.

.
:

o.

,
,
.

(adaptor molecule)
(. Grb2)
.

.
,
(. c-Src, PLC).

.

,
.
6
,
(upstream)
(downstream) .
SH2 SH3, Src (Src homology),

- Src. , C (phospholipase C, PLC)

p85 -3 (phosphati-

-18-

2:

dylinositole-3 kinase, PI3) ( ) . SH2

~100
. SH2- (SH2binding

site).

SH2-

SH2

SH3

SH2
.

.
7 ,

(Epidermal
Growth Factor Receptor, EGFR)
EGFR ErbB, ErbB-2
(HER-2/Neu), ErbB-3 (HER-3) ErbB-4 (HER-4) 8 .
( -
EGF)
-,

Ras-Raf-MEK-ERK
PI3K-PDK1-Akt, ,
. , EGFR

, , , 9 .
(transactivation)

-19-

2:

,
10, 11 .

3. EGFR.

EGFR
, ,
12,

13

, ErbB
14 .
,

15,

16

, , ,
, , , ,
40%

-20-

2:

17 .
/
EGFR ,
, ErbB
( HER-2)

EFGR

, , ,
18 .
, ATP,

EFGR,

19

,
EFGR
.
, ATP

.

- , ,

20

ErbB .
Gefitinib (ZD 1839, Iressa, AstaZeneca), ,
, EGFR ,
21 . in vitro

22 ,

23 .
Gefitinib -
Bcl-2,
BAD Gefitinib
24 . Gefitinib
25,

26

, EFGR
.
Gefitinib
in vitro in vivo ,
Gemcitabine 27 .

-21-

2:

28 . In vivo,
,
29 . ,
Gefitinib ,
placlitaxel 28.
Gefitinib
(
2002) ( 2003) -
- (non-small cell lung cancer,
NSCLC).

30 .

.
OSI-774 (Tarceva)
,
EGFR (intact) ,
in
vitro, p27kip1
G1 31 .
(upregulation) p27kip1
Rb
EGFR 32 . cisplatin
33 ,
, doxorubicin gemcitabine. ,
OSI-774 (effectors)

, EGFRvIII 34 . OSI774
.
Gefitinib
( , ).
EGFR
. PD-183805

ErbB .

-22-

in

2:

vitro

in

vivo

35 .
CI-1033 ,
SN-38 topotecan,
(drug transporter
breast

cancer

resistance

protein,

BCRP) 36 ,

CI-1033 SN-38 topotecan

CI-1033 gemcitabine 37 . CI-1033

PD-183805

,
38 . ,
PKI-166 EGFR/ErbB-2 ,

EGFR
/

ErbB-2 39

,
40 . ,

.
GW-572016 EGFR/ErbB-2

in vitro in vivo 41 .
,

42 ,
. EKB-569 EGFR

EGFR ErbB-2 in vitro in vivo 43 .

.

-23-

2:

AG-1478 44
,

(2-7)

EGFR

45 .

F
F
H

O
N

O
H

Cl
N

CH3O

O
O

Cl
N

ZD1839 (Iressa)

H
N

H
N

PD-183805
(CI-1033)

OSI-774
F

N
N

HO
N
H

PKI-166

H
N

Cl

CH3O
CH3O

EKB-569

Cl
N

N
AG-1478

4. EGFR.

HER2
HER2/neu
EGFR. neu,

46 ,
47 .

EGFR ( v-erbB) HER2 ( c-erbB) 48 .
HER2/neu, EGFR,

,
,

-, 49 . ,
-

-24-

2:

Src-2.
HER2/neu , (co-receptor) EGFRs.
- -
EGFRs,
EGFR (neuregulins),
HER3 (erbB3) HER4 (erbB4),

.
,
Ras, Src (PI-3K)/Akt
, JNK ERK
cAMP/ 50, 51 , 52 .
HER2
,

,
30% 53 . ,
HER2, ,

54 . HER2

,
55 .
HER2

.
-
(cyclin dependent kinases, CDKs) D1 (cyclin
D1),
G1 S . D1,
HER2/neu
(downstream target) 56 ,

-25-

2:

HER2/neu
HER2

G1
. , 57
p27Kip1, CDK cyclin
E-CDK2, c-Myc D, p27Kip1,

HER2.

HER2 cyclin
E/CDK2 p27Kip1. ,
HER2 G1/S
.
, PI-3K/Akt
HER2,
CDK p27Cip1

58

HER2 ,
, , ,
59 .
HER2
60 . , HER2

61 .

HER2
.

Herceptin

(Genentech), ,
HER2 .
FDA 1998

62

-.
Herceptin
15% 63 . Herceptin placlitaxel
doxorubicin ,

64 .

-26-

2:

ZD 1839, OSI-774 AG 1478

EGFR, GW 2016
EGFR HER2 IC50 12 nM 65 .

Cl
O

O
O

S
NH

N
N

5. GW-2016.

(Vascular

Epithelial Growth Factor, VEGF)

VEGF

,

.

VEGF-, , C, D, VEGF-F, VEGF-
(placenta growth factor,
PIGF) 66 .
VEGF
(VEGFRs) .
- VEGF-, o
VEGFR-1 (fms-like tyrosine kinase Flt-1) o VEGFR-2 (kinase insert
domain-containing

receptor

KDR,

Flk-1,).

, VEGFR-3 (fms-like tyrosine kinase Flt-4)

VEGF- C, D , VEGFR-2,
67 . VEGF- PIGF
VEGFR-1, VEGF-

-27-

2:

VEGFR-2 68 . VEGFR-2
69 .
PDGF
,

-,
.
VEGFR-1, ,
, 70 .
,

.
VEGFR-2.
VEGFR-2,
.
VEGF- ,
PLC SH2 -
71 . , PLC
C (PKC)
Ras-MEK-MAP.
, VEGFR-2 VEGF-,
PI3K/Akt,

72 . VEGFR-2 VEGF-,
()
(human umbilical vein endothelial
cells, HUVECs) 73 , (sprouting)

in

vitro

in

vivo.

, VEGF-
(eNOS) 74 , , ,

(ruffling),

VEGFR-2.

-28-

2:

6. VGFR-2.

O VEGFR-3, ,
,

.
,
, VEGFR-3

75

VEGFR-3

,
. , 1-2 mm
de novo
.
VEGF
. VEGF,

VEGFR-2,

-29-

2:

,

,

76 .

, ,
VEGF FGF.

VEGFR

. Semaxanib (SU5416) 77 ,
-2-,
Flk-1
78 .
doxorubicin ,
79 . ,
cisplatin gemcitabine

80 .

( ,

24 )
, VEGFR
.
PTK787/ZK222584 (Novartis Pharmaceuticals, USA
81 ), ZD 4190 ZD 6474 (AstaZeneca, UK 82 )

83 ),

CEP

5214

(Cephalon,

UK

VEGFR

.
BIBF1000 VEGFR-2

84 ,

VEGF 85

VGA1102

. SU6668 (SUGEN
Inc., USA) -2- 86 ,

-30-

2:

VEGFR/PDGFR/FGFR (fibroplast growth factor) 87

.

H
N

Cl

N
N N

Br

HN
NH

O
N

N
N

HO
CEP 5214

ZD 4190

PTK787/ ZK222584

Br

HN
O

COOH

HN
N
H

N
ZD 6474

SU 6668

7. VGFR.

Ras/MAPK
, . EGF PDGF.
Ras , Grb2,
, . Grb2
SOS
Ras. Ras Raf
/-,

MEK,

MAP

(mitogen kinase kinase, MAP kinase

kinase).
(MAP kinase pathway).

-31-

2:

, .

.
Ras , Raf,
-3 (phosphoinositide 3-kinases,
PI-3) RalGDS (RalGDS proteins),
.
, Rin1, AF6, p120-GAP, NF1GAP, MEKK1, Nore-1 Canoe
88, 89 .

8. Ras.

Raf-1 Ras

Ras

-32-

2:

(extracellular signal-regulated kinases, ERKs).

Raf, 90 ,

Raf/MAPK

TGF
91 . ,
92 .
Ral-GDS (Ral GDP Dissociation Stimulator)
Ras
. Ral-GDS Ral

Ras

93 ,
Ral
.

PI-3K

-
PtdIns[4,5]P2)

(phospatidylinositol

3,4,5-

(phospatidylinositol

(3,4,5)-trisphosphate,

4,5-
(4,5)-bisphosphate,

PtIns(3,4,5)P3.

,
.
PI3K
, (protein kinase B, PKB),
p70 S6 , PI3K (PI3K dependent kinase),
Rac ARF-6
Tec - 94 .
PI3K, PtIns(3,4,5)P3,
Akt, -3
(glycogen synthase-3, GSK) c-Myc
D (cyclin D). , PtIns(3,4,5)P3
NF-B, p53
BAD 95 . PI3K ,
96 .

Ras

GTP

, Harvey, Kirsten (A B)
N-Ras,

-33-

2:

, ,
89 .
,
GTP

GDP 97 .

Ras

.
Ras
. Ras
GTP
Ras . ,
Ras
,

Ras .

Ras

,
.
Ras
.
ras, ,

15-30% , ras

40 90% 98 .

Kirsten-ras

N-ras

Harvey-ras

. ras
,

, , .

Ras

Ras
99 .
Ras

-34-

2:

Ras
. , ,
Ras,
MAP 100 .
Ras .
, ,
(farnesyltransferse inhibitors, FTIs).
Ras

101 .
-,
(farnesyl diphosphate,
FPP)
CaaX (C: , cysteine, a:
, : -)
102 .

transferase,

FPT)

Ras

(farnesyl

protein

. , Ras
,
103 . ,
FTP
Ras. FTIs


.
:
A FPP, FPP
FPT
CaaX ,
CaaX Ras FTP.
, .
(bisubstrate inhibitors).

-35-

2:

, CaaX
104,

105

. CaaX

L739750 (Merck, FTase IC50 = 1.8 nM) FTI-276 (Hamilton & Sebti
groups, IC50 = 0.6 nM) 106 L744832

FTI-277

in

vivo

,
,

. , AZD3409 (AstraZeneca),

, 107 .

, ,
- CaaX FT-1 (Merck, Ftase IC50 = 1 nM) 108
4-() FT-2 (Ftase IC50 = 0.15
nM) 109 . - FT-1

FT-2

110

. L778123 (Ftase IC50 = 2

nM) H-ras IC50

= 15 nM. ATP
GCTase-I (GCTase-I IC50 = 100 nM)
GGPP CaaX 111 .
FTIs
Fase.
,
FT-3
(Fase IC50 = 0.2 nM)
112 . Bristol-Myers
Squib

FT-1,

,
,
FT-4 (Fase IC50 = 24 nM).
FTIs .
, Schering-Plough
SCH-37370 (Fase IC50 = 27000 nM)

-36-

2:

-
SCH-4432 (Fase IC50 = 250 nM) SCH-66336
(Fase IC50 = 1.9 nM)

113

, .

Jansen Research Foundation

JRF-1 (Fase IC50 = 180 nM) 114
JRF-2

(R115777,

=tripifarnib, ZARNESTRA, Fase IC50 = 0.86 nM) FTI

115
NIH 3T3 H-ras

IC50

1.7

nM.

75% 53 HTLs,
IC50 10 nM 116 ,
FTI
.
FTI ,
117 .


FTase.

ras

Ras .


Ras

(phospholipase D, PLD), (choline kinase, ChoK)

- (phosphocholine cytidyltransferase, CT) ,

Ras. ChoK
Ras-
,
118 .

-37-

2:

HS
HS
H
N

H2N

H
N

HS

O
OH

H
N

H2N

H
N

H
N

H2N

H
N

OH

O
SO2CH3

SO2CH3

L739750

SCH3

L744832

FTI-276

O
HS

SCH3

S
H
N

H2N

H
N

N
H

OCH3

H
N

HS

N
H

SCH3

H2N

O
AZD-3409

FTI-277

FT-1

O
N
N

SCH3
N
H

N
O

NC

NH

Cl

OH

N
H

NC

CN

FT-2

L778123

FT-3

CF3

Cl

Cl

Br

Cl

N
O

N
N
FT-4

SCH-37370

SCH-4432

SCH-66336

Cl
N

Cl

N
H2N

Cl
HN

N
O

JRF-1

JRF-2

9. FTIs.

Hemicholinium-3

(HC-3),

ChoK

119

ChoK.

-38-

2:

120

121 ,
,

122 .

),

1,2--p-(-

4-

,
ChoK, . ChoK-1 123 . ,
4

124

- , -ChoK
, ChoK-2,

ChoK 125 . ,
, (3-6)
(bispyridinium cyclophane)

. ,
,
ChoK-6,
ChoK 126 .
ChoK
,
127 .

-39-

2:

R4
O OH

2 Br

HO O

N
HC-3

N
ChoK-1
R4
NH

NH

2 Br

2 Br
N

R4

R4

R = H,
ChoK-2

Br
N

ChoK-3 (p,p)
ChoK-4 (m,m)
ChoK-5 (p,m)
ChoK-6 (m,p)

R4

10. ChoKs.

(Platelet
Derived Growth Factor, PDGF)
, PDGF Kit
PDGF .
5 like-Ig
-,

100

, PDGFR-
PDGFR-,
PDGF-A / PDGF-.
: ,
, 128 . PDGFR

,
129 .
(loop)
. , PDGF-,

-40-

130

2:

(neovascularization)

Kit

131 ,
, (stem cell factor, SCF),

132

Kit

. , Kit

133 , Kit

134

. , Kit

135 ,
.

Bcr-Abl
98 - ,
58 - 32

136 ,

,
.
- -
Bcr-Abl. (fussion protein),
(Philadelphia, Ph)
( t(9;22)).
,
(chronic myelogenous
leukemia,

CML),

(acute lymphoblastic leukemia, ALL)

137. c-abl,
- - 9,
(breakpoint cluster gene, bcr)
22. , Bcr-Abl,
- Abl,

-41-

2:

Ph+. Abl
,
DNA , Bcr-Abl
,
137 .
1990,
, (tyrphostins)
AG 1112, AG 1318 AG 957 138,

139

K562, (purging)
Ph+ ,
anti-Fas, 140 .

CML
.

HN

COOCH3

OH

HN

NH2

CN

CN
N

N
H

OH
AG 957

AG 112

AG 1318

H
N

NH2
CN

CN
N
H

N
O

N
CGP 57148 / STI 571 / Gleevec

11. Bcr-Abl.

Duker and Lydon ,

141

CGP

57148

-42-

(Ciba-Geigy),

2STI

2:

571/Gleevec/Glivec
142 CML.
Gleevec c-abl Bcr-Abl,
Bcr-Abl
143 . ,
, , , ,
,

144 .

, PDGF

c-Kit.

Gleevec,

, CML
Bcr-Abl. Gleevec

(gastrointestinal stromal tumor, GIST) 145 . ,
, ,
146 .

, .
Bcr-Abl

Gleevec. Bcr-Abl

,
.


Bcr-Abl . ,
, 147 .

-43-

2:

12. Bcr-Abl Gleevec.

(Fibroplast Growth Factors Receptor, FGFR )

(FGFs)

.
23 . FGFs
, FGFRs,
,
. FGFRs :
,

FGFs.
FGFs,
FGF (basic FGF, bFGF), FGF-2,
FGF 148 .
bFGF

,
(extracellular matrix, ECM) 149 .
bFGF.
.
FGF-1, FGF (acidic FGF),
FGF-8,
(androgen-induced growth factor, aFGF) FGF-13. bFGF,

-44-

2:

FGF-1, 9 FGF-11-14

. FGFs
,
FGF
150 .
(nuclear location signals, NLS) FGF-1, FGF-3
FGF-11FGF-14 151 .
NLS FGFs.
FGFs
152 .
FGFs

153 .

ECM.
VEGF, FGF
. FGFs
,
154 . ,

.
bFGF 155 ,

156 .
FGFs
-. FGFRs
, FGFR1 (flg), FGFR2 (bek), FGFR3
FGFR4 55% 72%
152. FGFRs
,

157 .

(immunoglobulin-like
domains) IgI, IgII IgIII,
(acidic region).

-45-

2:

-.
-

FGFR.

13. FGFR.

,
. -
.
,
: ,
MAP
PKC, , myc fos.

.
FGFs
ECM.

-46-

2:

FGFs ECM: ,
, ,

CM,

FGFs 158 .
FGF (FGF-binding protein, FGF-BP),
FGF
159 . FGF-BP
,
,
160 .
FGFs
,
,
.
FGFs
161 . FGF-1, FGF-2
FGF-8b
. ,
, FGFRs
,
162 .
FGFs
.
FGFRs ,
, (splicing),
FGFRs

.
FGFR ,
,

163

. FGFR-3

164 .
FGFRs
,
,
. (suramin),

-47-

2:

(complexes heparin-binding growth factors),
FGF-2,
FGF-2

activator) 165 .

(urokinase-plasminogen

. FGFRs
FGF-2 (saporin),

FGFR 166 .

FGFR

. ATP

FGFRs 167 .
SU9902 SU9803 (Sugen),
FGFR-1 VEGF 168 .
SU6668

FGFRs

.
169 .
, PD166285
FGFR-1, PDGFR c-Src .

,
PD173074, FGFR-1
-, PDGFR,
EGFR c-Src 170 .

-48-

2:

N
Cl

COOH
HN
N
H

O
N
H

SU 6668

Cl

PD166285
N

N
N

N
H

N
H

O
N

NH
O

PD173074

N
H

14. FGFR.

Cross M., Dexter T.M., Growth factors in development,

transformation, and tumorigenesis, Cell, 271-280, 64, 1991.

Peptide growth factors and their receptors, In: Sporn M.B., Roberts
A.B., (Eds), Handbook of Experimental Pharmacology, Vol. 95,
Springer-Verlag, Berlin, 1990.

Taylor S.S., Knighton D.R., Zheng J., TenEyck L.F., Sowadski J.,
Structural framework for the protein kinase family, Annu. Rev. Cell
Biol., 429-462, 8, 1992.

Van der Geer P., Hunter T., Lindberg R. A., Receptor protein
tyrosine-kinases and their signal transduction pathways, Ann. Rev.
Cell Biol., 251-337, 10, 1994.

Heldin C., Dimerization of cell surface

transduction, Cell, 213-223, 80, 1995.

Koch C.A. et al, SH2 and SH3 domains: elements that control
interactions of cytoplasmic signaling proteins, Science, 668-674,
252, 1991.

-49-

receptors

in

signal

2:

Yarbro J.W., Oncogenes and cancer suppressor genes, Semin.

Oncol. Nurs. 30-39, 8, 1992.

Yarden Y., Sliwkowski M.X., Untangling the ErbB signaling network,

Nat. Rev.Mol. Cell Biol., 127-137, 2, 2001.

Carpenter G., Employment of the epidermal growth factor receptor

in growth factor-independent signaling, J. Cell Biol., 697-702, 146,
1999.

10

Pinkas-Kramamrski R., Soussan L., Wanf et al., Diversification of

Neu differantiation factor signaling by combinatorial receptor
interactions, EMBO J., 2452-2467, 15, 1996.

11

Riese D.J. 2nd, van Raaij T. M., Plowman G.D. et al., The cellular
response to neuregulins is governed by complexation interactions of
the erbB receptor family, Mol. Cell Biol., 5770-5776, 15, 1995.

12

Miettinen P.J., Berger J.E., Meneses J. et al., Epithelial immaturity

and multiorgan failure in mice lacking epidermal growth factor
receptor, Nature, 337-341, 376, 1995.

13

Threadgill D.W., Dlugosz A.A., Hansen L.A. et al., Targeted

disruption of mouse EGF receptor: effect of genetic background on
mutant phenotype, Science, 230-234, 269, 1995.

14

Troyer K.L., Lee D.C., Regulation of mouse mammary gland

development and tumorigenesis by the ErbB signaling network, J.
Mammary Gland Biol. Neoplasia, 7-21, 6, 2001.

15

Salomon D.S., Brandt R., Ciardiello F. et al., Epidermal growth

factor-related peptides and their receptors in human malignancies,
Crit. Rev. Oncol. Hematol., 183-232, 19, 1995.

16

Tang C.K., Gong X.Q., Moscatello D.K., Wong A.J., Lippman M.E.,
Epidermal growth factor receptor vIII enhances tumorigenicity in
human breast cancer, Cancer Res., 3081-3087, 60, 2000.

17

Sauter G., Maeda T., Waldman F.M. et al, Patterns of epidermal

growth factor receptor amplification in malignant gliomas, Am. J.
Pathol., 1047-1053, 148, 1996.

18

Woodburn J.R., The epidermal growth factor receptor and its

inhibition in cancer therapy, Pharmacol. Ther., 241-250, 82, 1999.

19

Honegger A.M., Dull T.J., Felden S. et al, Point mutation at the ATP
binding site of EGF receptor abolishes protein-tyrosine kinase activity
and alters cellular routing, Cell, 199-209, 51, 1987.

20

Noonberg S.B., Benz C.C., Tyrosine kinase inhibitors targeted to the

epidermal growth factor subfamily: role as anticancer agents, Drugs,
753-767, 59, 2000.

21

Arteaga C.L., Johnson D.H., Tyrosine kinase inhibitors-ZD1839

(Iressa), Curr. Opin. Oncol., 491-498, 13, 2001.

22

Ciardello F., Caputo R., Bianco R et al., Antitumor effect and

potentiation of cytotoxic drugs activity in human cancer cells by ZD1839 (Iressa), an epidermal growth factor receptor-selective tyrosine
kinase inhibitor, Clin. Cancer Res., 2053-2063, 6, 2000.

-50-

2:

23

Janmaat M.L., Kruyt F.A., Rodriguez J.A. et al., Response to

epidermal growth factor receptor inhibitors in non-small cell lung
cancer cells: limited antiproliferative effects and absence os apoptosis
associated with persistent activity of extracellular signal-regulated
kinase or Akt kinase pathways, Clin. Cancer Res., 2316-2326, 9,
2003.

24

Gilmore A.P., Valentijn A.J., Wang P. et al., Activation of BAD by

therapeutic inhibition of epidermal growth factor receptor and
transactivation by insulin-like growth factor receptor, J. Biol. Chem.
2764327650, 277, 2002.

25

Magne N, Fischel J.L., Dubreuil A. et al., Influence of epidermal

growth factor receptor (EGFR), p53 and intrinsic MAP kinase pathway
status of tumour cells on the antiproliferative effect of ZD1839
("Iressa"), Br. J. Cancer, 15181523, 86, 2002.

26

Moasser M.M., Basso A., Averbuch S.D. et al., The tyrosine kinase
inhibitor ZD1839 ("Iressa") inhibits HER2-driven signaling and
suppresses the growth of HER2-overexpressing tumor cells, Cancer
Res., 71847188, 61, 2001.

27

Sirotnak F.M., Zakowski M.F., Miller V.A. et al., Efficacy of cytotoxic

agents against human tumor xenografts is markedly enhanced by
coadministration of ZD1839 (Iressa), an inhibitor of EGFR tyrosine
kinase, Clin. Cancer Res., 48854892, 6, 2000.

28

Huang S.M., Li J., Armstrong E.A. et al., Modulation of radiation

response and tumor-induced angiogenesis after epidermal growth
factor receptor inhibition by ZD1839 (Iressa), Cancer Res., 4300
4306, 62, 2002.

29

Hirata A., Ogawa S., Kometani T. et al., ZD1839 (Iressa) induces

antiangiogenic effects through inhibition of epidermal growth factor
receptor tyrosine kinase, Cancer Res., 25542560, 62, 2002.

30

Ranson M., Hammond L.A., Ferry D. et al., ZD1839, a selective oral

epidermal growth factor receptor-tyrosine kinase inhibitor, is well
tolerated and active in patients with solid, malignant tumors: results
of a phase I trial, J. Clin. Oncol., 22402250, 20, 2002.

31

Moyer J.D., Barbacci E.G., Iwata K.K. et al, Induction of apoptosis

and cell cycle arrest by CP-358,774, an inhibitor of epidermal growth
factor receptor tyrosine kinase, Cancer Res., 48384848, 57, 1997.

32

Busse D., Doughty R.S., Ramsey T.T. et al., Reversible G(1) arrest
induced by inhibition of the epidermal growth factor receptor tyrosine
kinase requires up-regulation of p27(KIP1) independent of MAPK
activity, J. Biol. Chem., 69876995, 275, 2000.

33

Pollack V.A., Savage D.M., Baker D.A. et al., Inhibition of epidermal

growth factor receptor-associated tyrosine phosphorylation in human
carcinomas with CP-358,774: dynamics of receptor inhibition in situ
and antitumor effects in athymic mice, J. Pharmacol. Exp. Ther.,
739748, 291, 1999.

34

Lal A., Glazer C.A., Martinson H.M. et al., Mutant epidermal growth
factor receptor up-regulates molecular effectors of tumor invasion,
Cancer Res., 33353339, 62, 2002.

-51-

2:

35

Gieseg M.A., de Bock C., Ferguson L.R. et al., Evidence for epidermal
growth factor receptor-enhanced chemosensitivity in combinations of
cisplatin and the new irreversible tyrosine kinase inhibitor CI-1033,
Anticancer Drugs, 683690, 12, 2001.

36

Erlichman C., Boerner S.A., Hallgren C.G. et al., The HER tyrosine
kinase inhibitor CI1033 enhances cytotoxicity of 7-ethyl-10hydroxycamptothecin and topotecan by inhibiting breast cancer
resistance protein-mediated drug efflux, Cancer Res., 739748, 61,
2001.

37

Nelson J.M., Fry D.W., Akt, MAPK (Erk1/2), and p38 act in concert to
promote apoptosis in response to ErbB receptor family inhibition, J.
Biol. Chem., 1484214847, 276, 2001.

38

Levitzki A., Protein kinase inhibitors as a therapeutic modality, Acc.

Chem. Res., 462-469, 36, 2003.

39

Motoyama A.B., Hynes N.E., Lane H.A., The efficacy of ErbB

receptor-targeted anticancer therapeutics is influenced by the
availability of epidermal growth factor-related peptides, Cancer Res.
31513158, 62, 2002.

40

Mellinghoff I.K., Tran C., Sawyers C.L., Growth inhibitory effects of

the dual ErbB1/ErbB2 tyrosine kinase inhibitor PKI-166 on human
prostate cancer xenografts, Cancer Res., 52545259, 62, 2002.

41

Xia W., Mullin R.J., Keith B.R. et al., Anti-tumor activity of

GW572016: a dual tyrosine kinase inhibitor blocks EGF activation of
EGFR/erbB2 and downstream Erk1/2 and AKT pathways, Oncogene,
62556263, 21, 2002.

42

Belanger M., Jones C.M., Germond C. et al, A phase II, open-label,

multicenter study of GW572016 in patients with metastatic colorectal
cancer refractory to 5-FU in combination with irinotecan and/or
oxaliplatin, Proc. Am. Soc. Clin. Oncol., 978a, 22, 2003.

43

Wissner A., Brawner Floyd M.B., Rabindran S.K. et al., Syntheses

and EGFR and HER-2 kinase inhibitory activities of 4-anilinoquinoline3-carbonitriles: analogues of three important 4-anilinoquinazolines
currently undergoing clinical evaluation as therapeutic antitumor
agents, Bioorg. Med. Chem. Lett., 28932897, 12, 2002.

44

Osherov N., Levitzki A., Epidermal-growth-factor-dependent

activation of the src-family kinases, Eur. J. Biochem., 1047-1053,
225, 1994.

45

Nagane M., Narita Y, Mishima K., Levitzki A., Burgess A. W., Cavenee
W. K., uang H. J., Human glioblastoma xenografts overexpressing
a tumor-specific mutant epidermal growth factor receptor sensitized
to cisplatin by the AG1478 tyrosine kinase inhibitor, J. Neurosurg.,
472-479, 95, 2001.

46

Shih C., Padhy L.C., Murray M., Weinberg R.A., Transforming genes
of carcinomas and neuroblastomas introduced into mouse
fibroblasts, Nature, 261-264, 290, 1981.

47

Hung M.C., Schechter A.L., Chevray P.Y.M., Stern D.F., Weinberg

R.A., Molecular cloning of the neu gene: Absence of gross structural

-52-

2:

alteration in oncogenic alleles, Proc. Natl. Acad. Sci. USA, 261-264,

83, 1986.
48

Semba K., Kamata N., Toyoshima K., Yamamoto T., A v-erbBrelated protooncogene, c-erbB-2, is distinct from the c-erbB1/epidermal growth factor-receptor gene and is amplified in a human
salivary gland adenocarcinoma, Proc. Natl. Acad. Sci. USA., 64976501, 82, 1985.

49

Bargmann C.I., Hung M.C., Weinberg R.A., The neu oncogene

encodes an epidermal growth factor receptor-related protein,
Nature, 226230, 319, 1986.

50

Zwick E, Wallasch C., Ullrich A., HER2/neu: a target for breast

cancer therapy, Breast Dis., 7-18, 11, 2000.

51

Grant S., Qiao L., Dent P., Roles of erbB family receptor tyrosine
kinases, and downstream signaling pathways, in the control of cell
growth and survival, Front. Biosci., 376389, 7, 2002.

52

Zhou B.P., Liao Y., Xia W., Zou Y., Spohn B., Hung M.C., HER2/neu
induces p53 ubiquitination via Akt-mediated MDM2 phosphorylation,
Nat. Cell Biol., 973982, 3, 2001.

53

Slamon D.J., Godolphin W., Jones L.A., Holt J.A., Wong S.G., Keith
D.E., Levin W.J., Stuart S.G., Udove J., Ullrich A., Press M.F.,
Studies of the HER-2/neu proto-oncogene in human breast and
ovarian cancer, Science, 707-771, 244, 1989.

54

Paik S., Hazan R., Fisher E.R., Sass R.E., Fisher B., Redmond C.,
Schlessinger J., Lippman M.E., King C.R, Pathologic findings from the
national surgical adjuvant breast and bowel project: prognostic
signi.cance of erbB-2 protein overexpression in primary breast
cancer, J. Clin. Oncol., 103112, 8, 1990.

55

Brennan P.J., Kumogai T., Berezov A., Murali R., Greene M.I.,
HER2/neu: Mechanisms of dimerization/oligomerization, Oncogene,
60936101, 19, 2000.

56

Lee R.J., Albanese C., Fu M., DAmico M., Lin B., Watanabe G., Haines
G.K., Siegel P.M., Hung M.C., Yarden Y., Horowitz J.M., Muller W.J.,
Pestell R.G., Cyclin D1 is required for transformation by activated
Neu and is induced through an E2F-dependent signaling pathway,
Mol. Cell. Biol., 672683, 20, 2000.

57

Lane H.A., Beuvink I., Motoyama A.B., Daly J.M., Neve R.M., Hynes
N.E., ErbB2 potentiates breast tumor proliferation through
modulation
of
p27Kip1Cdk2
complex
formation:
receptor
overexpression does not determine growth dependency, Mol. Cell.
Bio., 32103223, 20, 2000.

58

Zhou B.P., Liao Y., Xia W., Spohn B., Lee M.-H., Hung M.-C.,
Cytoplasmic
localization
of
p21Cip1/WAF1
by
Akt-induced
phosphorylation in HER2/nwu-overexpressing cells, Nat. Cell Biol.,
245252, 3, 2001.

59

Hynes N.E., Stern D.F., The biology of erbB-2/neu/HER-and its role

in cancer, Biochim. Biophys. Acta, 165184, 1198, 1994.

-53-

2:

60

Cooke T., Reeves J., Lannigan A., Stanton P., The value of the
human epidermal growth factor receptor-2 (HER2) as a prognostic
marker, Eur. J. Cancer, 310, 37, 2001.

61

Yu D., Hung M.C., Overexpression of ErbB2 in cancer and ErbB2

targeting strategies, Oncogene, 61156121, 19, 2000.

62

Pegram M.D., Lipton A., Hayes D.F., Weber B.L., Baselga J.M.,
Tripathy D., Baly D., Baughman S.A., Twaddell T., Glaspy .JA.,
Slamon D.J., Phase II study of receptor-enhanced chemosensitivity
using recombinant humanized anti-p185HER2/neu monoclonal
antibody plus cisplatin in patients with HER2/neu-overexpressing
metastatic breast cancer refractory to chemotherapy treatment, J.
Clin. Oncol., 26592671, 16,1998.

63

Cobleigh M.A., Vogel C.L., Tripathy D., Robert N.J., Scholl S.,
Fehrenbacher L., Wolter J.M., Paton V., Shak S., Lieberman G.,
Slamon D.J, Multinational study of the efficacy and safety of
humanized anti-HER2 monoclonal antibody in women who have
HER2-overexpressing metastatic breast cancer that has progressed
after chemotherapy for metastatic disease, J. Clin. Oncol., 2639
2648, 17, 1999.

64

Stebbing J., Copson E., OReilly S., Herceptin (trastuzamab) in

advanced breast cancer, Cancer Treat. Rev., 287290, 26, 2000.

65

Keith B.R., Allen P.P., Aliigood K.J., Crosby R.M., Lackey K., Gilmer T.
M., Mullin R.J., Abstract 4308, Proceedings of 92nd Annual Meeting
AACR, 2428 March 2001, New Orleans, LA, USA.

66

Ferrara N., Vascular endothelial growth factor: molecular and

biological aspects, Curr. Top. Microbiol. Immunol., 1-30, 237, 1999.

67

Joukov V., Pajusola K., Kaipainen A., Chilov D., Lahtinen I., Kukk E.,
Saksela O., Kalkkinen N., Alitalo K., A novel vascular endothelial
growth factor, VEGF-C, is a ligand for the Flt4 (VEGFR-3) and KDR
(VEGFR2) receptor tyrosine kinases, EMBO J., 290-298, 15, 1996.

68

Eriksson U., Alitalo K., Structure, expression and receptorbinding

properties of novel vascular endothelial growth factors, Curr. Top.
Microbiol. Immunol., 41-57, 237, 1999.

69

Cross M.J., Claesson-Welsh L., FGF and VEGF function in

angiogenesis: signalling pathways, biological responses and
therapeutic inhibition, Trends Pharmacol. Sci., 201-207, 22, 2001.

70

List A., Vascular endothelial growth factor signaling pathway as an

emerging target in hematologic malignancies, Oncologist, 24-31, 6
(Suppl 5), 2001.

71

Takahashi T., Yamaguchi S., Chida K., Shibuya M., A single

autophosphorylation site on KDR/Flk-1 is essential for VEGF-Adependent activation of PLC and DNA synthesis in vascular
endothelial cells, EMBO J., 276878, 20, 2001.

72

Gerber H.P., McMurtrey A., Kowalski J., Yan M., Keyt B.A., Dixit V.,
Ferrara N., Vascular endothelial growth factor regulates endothelial
cell survival through the phosphatidylinositol 3-kinase/Akt signal
transduction pathway. Requirement for Flk-1/KDR activation, J. Biol.
Chem., 3033643, 273, 1998.

-54-

2:

73

Kroll J., Waltenberger J., A novel function of VEGF receptor-2 (KDR):

rapid release of nitric oxide in response to VEGF-A stimulation in
endothelial cells, Biochem. Bioph. Res. Commun., 636639, 265,
1999.

74

Shen, B.Q., Lee, D.Y., Zioncheck, T.F., Vascular endothelial growth

factor governs endothelial nitric-oxide synthase expression via a
KDR/Flk-1 receptor and a protein kinase C signalling pathway, J.
Biol. Chem., 3305733063, 274 1999.

75

Witmer, A.N., Dai, J., Weich, H.A., Vrensen, G.F., Schlingemann,

R.O., Expression of vascular endothelial growth factor receptors 1, 2,
and 3 in quiescent endothelia, J. Histochem. Cytochem., 767778,
50, 2002.

76

Boehm T., Folkman J., Browder T., O'Reilly M.S., Antiangiogenic

therapy of experimental cancer does not induce acquired drug
resistance, Nature, 404-407, 390, 1997.

77

Sun L., Tran N., Tang F., Harald A., Hirth P, McMahon G., Tang C.,
Synthesis and biological evaluations of 3-substituted Indolin-2-ones:
A novel class of tyrosine kinase inhibitors that exhibit selectivity
toward particular receptor tyrosine kinases, J. Med Chem., 25882603, 41, 1998.

78

Ellis L.M., Takahashi Y., Liu W., Shaheen R.M., Vascular endothelial
growth factor in human colon cancer: Biology and therapeutic
implications, Oncologist, 11-15, 5 (Suppl 1), 2000.

79

Overmoyer B., Robertson K., Person M., Shenk R., Lewin J.,
Jesberger J., Ziats N., Tserng K., Hoppel C., Hartman P. et al., A
phase I pharmacokinetic and pharmacodynamic study of SU 5416 and
doxorubicin in inflammatory breast cancer, Abstract 31, Proceedings
of 92nd Annual Meeting AACR, 2428 March 2001, New Orleans, LA,
USA.

80

Marx G.M., Steer C.B., Harper P., Pavlakis N., Rixe O., Khayat D.,
Unexpected serious toxicity with chemotherapy and antiangiogenic
combinations: Time to take stock! J. Clin. Oncol., 1446-1448, 20,
2002.

81

Drevs J., Hofmann I., Hugenschmidt H., Wittig C., Madjar H., Muller
M., Wood J., Martiny-Baron G., Unger C., Marme D., Effects of
PTK787/222584, a specific inhibitor of vascular endothelial growth
factor receptor tyrosine kinases, on primary tumor, metastasis,
vessel density, and blood flow in a murine renal cell carcinoma
model, Cancer Res., 4819-4824, 60, 2000.

82

Wedge S.R., Ogilvie D.J., Dukes M., Kendrew J., Curwen J.O.,
Hennequin L.F., Thomas A.P., Stokes E.S., Curry B., Richmond G.H.
et al, ZD4190: an orally active inhibitor of vascular endothelial
growth factor signaling with broad-spectrum antitumor efficacy,
Cancer Res., 970-975, 60, 2000.

83

Hurwitz H.I., Eckhardt S.G., Holden S.N., Basser R., Deboer

R.,Rosenthal M., Rischin D., Swaisland H., Barge A., McKinley
M.,Wheeler C., A phase I study of ZD6474, an oral VEGF receptor
tyrosine kinase inhibitor, in patients with solid tumours, Abstract 5,

-55-

2:

Proceedings of AACR-NCI-EORTC Conference, 29 Oct.2 Nov., 2001,

Miami Beach, FL, USA.
84

Hell-Poumojib M., Hilberg F., Roth G., Heckel A., Van Meel J.,
BIBF1000: A novel and potent VEGFR-2 inhibitor inhibits
proliferation and induces apoptosis of endothelial cells in vitro,
Annual Meeting AACR, 2428
Abstract 23, Proceedings of 92nd
March, 2001, New Orleans, LA, USA.

85

Yamagishi T., Ueda Y., Samata K., Ikeya H., Hirayama N., Nakaike,
A
novel
low
molecular
weight
VEGF-receptor
binding
inhibitor,VGA1102, inhibits the VEGF functions and growth of human
tumour xenografts, Abstract 273, Proceedings of the 11th NCIEORTC-AACR Symposium, 710 Nov, 2000, Vrije Universitet,
Amsterdam, The Netherlands.

86

Sun L., Tran N., Liang C., Tang F., Rice A., Schreck R., Waltz K.,
Shawver L. K., McMahon G., Tang C., Design, synthesis, and
evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2ylmethylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF
receptor tyrosine kinases, J. Med. Chem., 5120-5130, 42, 1999.

87

Laird A.D., Christensen J.G., Li G., Carver J., Smith K., Xin X., Moss
K.G., Louie S.G., Mendel D.B., Cherrington J.M., SU6668 inhibits Flk1/KDR and PDGFRbeta in vivo, resulting in rapid apoptosis of tumor
vasculature and tumor regression in mice, FASEB J., 681-690, 16,
2002.

88

Campbell S. L., et al., Increasing complexity of Ras signalling,

Oncogene, 1395-1413, 17, 1998.

89

Ramirez-De Molina A., Rodriguez-Gonzalez A., Lacal J.C., Targeting

new anticancer drugs within signalling pathways regulated by the Ras
GTPase superfamily, Int. J. Oncol., 517, 19, 2001.

90

Kerkhoff E., Fedorov L.M., Siefken R., Walter A.O., Papadopoulos T.,
Rapp U.R, Lung-targeted expression of the c-Raf-1 kinase in
transgenic mice exposes a novel oncogenic character of the wild-type
protein, Cell Growth Differ., 185190, 11, 2000.

91

Janda E., Lehmann K., Killisch I., Jechlinger M., Herzig M., Downward
J., Beug H., Grunert S., Ras and TGF cooperatively regulate
epithelial cell plasticity and metastasis, dissection of Ras signaling
pathways, J. Cell Biol., 299313, 156, 2002.

92

Hamad N.M., Elconin J.H, Karnoub A.E., Bai W., Rich J.N., Abraham
R.T., et al., Distintc equirements for Ras oncogenesis in human
versus mouse cells, Genes Dev., 20452057, 16, 2002.

93

Urano T., Emky R., Feig L.A., Ral-GTPases mediate distinct

downstream signaling pathway from Ras that acilitates cellular
transformation, Eur. Mol. Biol. Org., 810816, 15, 1996.

94

Cantley L.C., The phosphoinositide 3-kinase pathway, Science,

16551657, 296, 2002.

95

Sabbatini P., McCormick F., Phosphoinositide-OH kinase (PI3K) and

PKB/Akt delay the onset of p53-mediated, transcriptionally dependent
apoptosis, J. Biol. Chem., 2426324269, 274, 1999.

-56-

2:

96

Barbadelli A., Basile M.L., Audero E., Giordano S., Wennstromn S.,
Menard S., et al., Concomitant activation of pathways downstream
of Grb2 and PI 3-kinase is required for MET-mediated metastasis,
Oncogene, 1139-1146, 18, 1999.

97

Van Aelst L, DSouza-Schorey C., Rho GTPases and signaling

networks, Genes Dev., 2295-2322, 11, 1997.

98

Bos J.L., Ras oncogenes in human cancer: A review, Cancer Res.,

46824689, 49, 1989.

99

Kloog Y., Cox A.D., Sinensky M., Concepts in Ras-directed therapy,

Expert. Opin. Investig. Drugs, 21212140, 8, 1999.

100

Sebolt-Leopold J.S., Development of anticancer drugs targeting the

MAP kinase pathway, Oncogene, 65946599, 19, 2000.

101

Glomset J.A., Farnsworth CC., Role of protein modification reactions

in programming interactions between ras-related GTPases and cell
membranes, Annu. Rev. Cell Biol., 181205, 10, 1994.

102

F.L. Zhang, P. J. Casey, Protein Prenylation: Molecular mechanisms

and functional consequences, Annu. Rev. Biochem., 241-269, 65,
1996.

103

Jackson J.H., Cochrane C.G., Bourne J.R., Solski P.A., Buss J.E., Der
C.J., Farnesol modification of Kirsten-ras exon 4B protein is essential
for transformation, Proc. Natl. Acad. Sci. USA, 30423046, 87,
1990.

104

Leonard D.M., Ras Farnesyltransferase: A new therapeutic target., J.

Med. Chem., 2971-2990, 40, 1997.

105

Sebti S. M., Hamilton, A. D., New Approaches to anticancer drug

design based on the inhibition of farnesyltransferase, Drug Discov.
Today, 26-33, 3, 1998.

106

Lerner E.C., Qian Y., Blaskovich M.A., Fossum R.D., Vogt A., Sun, J.,
Cox A.D., Der C.J., Hamilton A.D., Sebti S.M., Ras CAAX
peptidomimetic FTI-277 selectively blocks oncogenic Ras signaling by
inducing cytoplasmic accumulation of inactive Ras-Raf complexes, J.
Biol. Chem., 26802-26806, 270, 1995.

107

Stephens T.C., Wardleworth M.J., Matusiak Z.S., Ashton S.E., Hancox

U.J., Bate M., Ferguson R., Boyle T., AZD3409, a novel, oral, protein
prenylation inhibitor with promising preclinical antitumor activity,
Abstract R4870, Proc. Am. Assoc. Cancer Res., 970, 44, 2003.

108

Williams T.M., Ciccarone T.M., MacTough S.C., Bock R.L., Conner

M.W., Davide J.P., Hamilton K., Koblan K.S., Kohl N.E., Kral A.M.,
Mosser S.D., Omer C.A., Pompliano D.L,, Rands E., Schaber M.D.,
Shah D., Wilson F.R., Gibbs J.B., Graham S.L., Hartman G.D., Oliff
A.I., Smith R.L., 2-Substituted piperazines as constrained amino
acids. Application to the synthesis of potent, non carboxylic acid
inhibitors of farnesyltransferase, J. Med. Chem., 1345-1348, 39,
1996.

109

Anthony N.J., Gomez R.P., Schaber M.D., Mosser S.D., Hamilton

K.A., ONeill T.J., Koblan K.S., Graham S.L., Hartman G.D., Shah D.,
Rands E., Kohl N.E., Gibbs J.B., Oliff A.I., Design and in vivo analysis

-57-

2:

of potent nonthiol inhibitors of farnesyl protein transferase, J. Med.

Chem., 3356-3368, 42, 1999.
110

Williams T. M., Bergman J. M., Brashear K., Breslin M. J, Dinsmore C.

J., Hutchinson J.H., MacTough S.C., Stump C.A., Wei D.D., Zartman
C.B., et al, N-Arylpiperazinone inhibitors of farnesyltransferase:
Discovery and biological activity, J. Med. Chem., 3779-3784, 42,
1999.

111

Huber H.E., Robinson, R.G., Watkins A., Nahas, D.D., Abrams, M.T.,
Buser, C.A., Lobell, R.B., Patrick D., Anthony N.J., Dinsmore, C.J.,
Graham, S.L., Hartman G.D., Lumma W.C., Williams T.M., Heimbrook
D.C., Anions modulate the potency of geranylgeranyl-proteintransferase-I inhibitors, J. Biol. Chem., 24457-24465, 276, 2001.

112

Bell I.M., Gallicchio S.N., Abrams M., Beese L.S., Beshore D.C.,
Bhimnathwala H., Bogusky M.J., Buser C.A., Culberson J.C., Davide
J., 3-Aminopyrrolidinone farnesyltransferase inhibitors: Design of
macrocyclic compounds with improved pharmacokinetics and
excellent cell potency., J. Med. Chem., 2388-2409, 45, 2002.

113

Njoroge F.G., Taveras A.G., Kelly J., Remiszewski S., Mallams A. K.,
Wolin R., Afonso A., Cooper A.B., Rane D.F., Liu Y.-T., Wong J.,
Vibulbhan B., Pinto P., Deskus J., et al, (+)-4-[2-[4-(8-Chloro-3,10dibromo-6,11-dihydro-5H-benzo-5,6]cyclohepta[1,2-b]-pyridin11(R)-yl)-1-piperidinyl]-2-oxo-ethyl]-1-piperidinecarboxamide (SCH66336): A very potent farnesyl protein transferase inhibitor as a
novel antitumor agent, J. Med. Chem., 2125-2135, 42, 1999.

114

Ding C.Z., Batorsky R., Bhide R., Chao H.J., Cho Y., Chong S., GulloBrown J., Guo P., Kim S.H., Lee F., Discovery and structure-activity
relationships
of
imidazole-containing
tetrahydrobenzodiazepine
inhibitors of farnesyltransferase. J. Med. Chem. 5241-5253, 42,
1999.

115

Venet M., End D., Angibaud

P., Farnesyl protein transferase
inhibitor ZARNESTRA R115777s. History of a discovery, Curr. Top.
Med. Chem., 1095-1102, 3, 2003.

116

End D.W., Smets G., Todd A.V., Applegate T.L., Fuery C.J., Angibaud
P., Venet M., Sanz G., Poignet H., Skrzat S, Devine A., Wouters W.,
Bowden C., Characterization of the antitumor effects of the selective
farnesyl protein transferase inhibitor R115777 in vivo and in vitro,
Cancer Res., 131-137, 61, 2001.

117

Gelb M.H., Van Voorhis W.C., Buckner F.S., Yokoyama K., Eastman
R., Carpenter E.P., Panethymitaki C., Brown K.A., Smith D.F.,
Protein farnesyl and N-myristoyl transferases: Piggy-back medicinal
chemistry targets for the development of antitrypanosomatid and
antimalarial therapeutics, Mol. Biochem. Parasitol., 155-163, 126,
2003.

118

Lacal J.C., Choline kinase inhibitors: A novel target to search for

antitumor drugs, Drugs, 419426, 4, (2001).

119

Lloveras J., Hamza M., Chap H., Douste-Blazy L., Action of

hemicholinium-3 on phospholipid metabolism in Krebs II, ascites
cells, Biochem. Pharmacol., 39873993, 34, 1985.

-58-

2:

120

Hernandez-Alcoceba R., Fernandez F., Lacal J.C., In vivo antitumor

activity of choline kinase inhibitors: A novel target for anticancer drug
discovery, Cancer Res., 31123118, 59, 1999.

121

Cannon J.G., Structure-activity aspects of hemicholinium-3 (HC-3)

and its analogs and congeners, Med. Res. Rev., 505531, 14, 1994.

122

Ramirez de Molina A., Rodriguez-Gonzalez A., Penalva V., Lucas L.,

Lacal J.C., Inhibition of ChoK is an efficient antitumor strategy for
Harvey-, Kirsten-, and N-ras-transformed cells, Biochem. Biophys.
Res. Commun., 873879, 285, 2001.

123

Campos J., Nez M.C., Rodrguez V., Gallo M.A.., Espinosa A.,
QSAR
of
1,1-(1,2-ethylenebisbenzyl)bis(4substitutedpyridinium)dibromides as choline kinase inhibitors: A
different approach for antiproliferative drug design, Bioorg. Med.
Chem. Lett., 767-770, 10, 2000.

124

Campos J., Nez M.C., Snchez R.M., Gmez-Vidal J.A., RodrguezGonzlez A., Bez M., Gallo M, Lacal J.C., Espinosa A., Quantitative
structure-activity relationships for a series of symmetrical
bisquaternary anticancer compounds, Bioorg. Med. Chem. 22152231, 10, 2002.

125

Conejo-Garca A., Campos J., Snchez R.M., Rodrguez-Gonzlez A.,

Lacal J.C., Gallo M., Espinosa A., Choline kinase inhibitory effect and
antiproliferative
activity
of
new
1,1,1-(benzene-1,3,5triylmethylene)tris{4-[(disubstituted)amino]pyridinium} tribromides,
Eur. J. Med. Chem., 109-116, 38, 2003.

126

Conejo-Garca ., Campos J., Snchez-Martn R.M., Gallo M.,

Espinosa A., Bispyridinium cyclophanes: Novel templates for human
choline kinase inhibitors, J. Med. Chem., 37543757, 46, 2003.

127

Rodrguez-Gonzlez A, Ramirez de Molina A, Ferndez M.A., Ramos

M.C., Nez M.C., Campos J., et al, Inhibition of choline kinase as a
therapeutic modality as a specific cytotoxic strategy in oncogentransformed cells, Oncogene, 8803-8812, 22, 2003.

128

Heldin C.H., Ostman A., Ronnstrand L, Signal transduction via

platelet-derived growth factor receptors, Biochim. Biophys. Acta,
F79F113, 1378, 1998.

129

Hermanson M., Funa K., Hartman M., Claesson-Welsh L., Heldin C.H.,
Westermark B., Nister M., Platelet-derived growth factor and its
receptor in human glioma tissue: expression of messenger RNA and
protein suggests the presence of autocrine and paracrine loops
Cancer Res., 32133219, 52, 1992.

130

Dunn I.F., Heese O., Black P.M., Growth factors in glioma

angiogenesis: FGFs, PDGF, EGF, and TGFs, J. Neuroonc., 121137,
50, 2000.

131

Wang C., Curtis J.E., Geissler E.N., McCulloch E.A., Minden M.D., The
expression of the proto-oncogene c-kit in the blast cells of acute
myeloblastic leukaemia, Leukemia, 699702, 3, 1989.

132

Heinrich M.C., Dooley D.C., Freed A.C., Band L., Hoatlin M.E., Keeble
W.W., Peters S.T., Silvey K.V., Ey F.S., Kabat D., et al., Constitutive

-59-

2:

expression of steel factor gene by human stromal cells, Blood, 771

783, 82, 1993.
133

Krystal G.W., Hines S.J., Organ C.P., Autocrine growth of small cell
lung cancer mediated by coexpression of c-kit and stem cell factor,
Cancer Res., 370376, 56, 1996.

134

Moskaluk C.A., Tian Q., Marshall C.R., Rumpel C.A., Franquemont

D.W., Frierson H,F, Mutations of c-kit jm domain are found in a
minority of human gastrointestinal stromal tumors, Oncogene 1897
1902, 18, 1999.

135

Natali P.G, Berlingieri M.T., Nicotra M.R., Fusco A., Santoro E., Bigotti
A., Vecchio G., Transformation of thyroid epithelium is associated
with loss of c-kit receptor, Cancer Res.,, 17871791, 55, 1995.

136

Blume-Jensen P., Hunter T., Oncogenic kinase signalling, Nature

355365, 411, 2001.

137

Griffin J.D., Phosphatidyl inositol signaling by BCR/ABL:

Opportunities for drug development, Cancer Chemother. Pharmacol.,
S11S16, 48 (suppl 1), 2001.

138

Anafi M., Gazit A., Gilon C., Ben-Neriah Y., Levitzki A., Selective
interactions of transforming and normal abl proteins with ATP,
tyrosine-copolymer substrates, and tyrphostins, J. Biol. Chem. 451823, 267, 1992.

139

Kaur G., Gazit A., Levitzki A., Stowe E., Cooney D. A., Sausville, E.
A., Tyrphostin induced growth inhibition: Correlation with effect on
p210bcr-abl autokinase activity in K562 chronic myelogenous
leukaemia, Anticancer Drugs, 213-222, 5, 1994.

140

Carlo-Stella C., Regazzi E., Sammarelli G., Colla S., Garau D., Gazit
A., Savoldo B., Cilloni D., Tabilio A., Levitzki A., Rizzoli V., Effects of
the tyrosine kinase inhibitor AG957 and an Anti-Fas receptor antibody
on CD34(+) chronic myelogenous leukemia progenitor cells, Blood,
3973-3982, 93, 1999.

141

Druker B.J., Tamura S., Buchdunger E., Ohno, S., Segal G. M.,
Fanning S., Zimmermann J., Lydon N.B., Effects of a selective
inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive
cells, Nat. Med., 561-6, 2, 1996.

142

Druker B.J., Perspectives on the development of a molecularly

targeted agent, Cancer Cell, 31-36, 1, 2002.

143

Savage D.G., Antman K.H., Imatinib mesylate-a new oral targeted

therapy, N. Engl. J. Med., 683-693, 346, 2002.

144

Druker B.J., Talpaz M., Resta D.J., et al, Efficacy and safety of a
specific inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid
leukaemia, N. Engl. J. Med., 10311037, 344, 2001.

145

Heinrich, M.C., Griffith D.J., Druker, B.J., Wait, C.L., Ott, K.A., Zigler,
A.J., Inhibition of c-kit receptor tyrosine kinase activity by STI 571, a
selective tyrosine kinase inhibitor, Blood, 925-932, 96, 2000.

146

Gambacorti-Passerini C.B., Gunby R.H., Piazza R., Galietta A.,

Rostagno R., Scapozza L., Molecular mechanisms of resistance to

-60-

2:

imatinib in Philadelphia-chromosome-positive leukaemias, Lancet

Oncol., 7585, 4, 2003.
147

Griffin J.D., Resistance to targeted therapy in leukaemia, Lancet,

45859, 359, 2002.

148

Baird A., Bhlen P., Fibroblast growth factors. In: Sporn M.B.,
Roberts A.B., (Eds), Peptide growth factors and their receptors. I,
Springer, New York, 1991 pp. 368418.

149

Ornitz D.M., FGFs, heparansulfate and FGFRs: Complex interactions

essential for development, Bioessays, 108112, 22, 2000.

150

Vlodawsky I., Extracellular sequestration and release of fibroblast

growth factor: A regulatory mechanism?, Trends Biochem. Sci. 268
271, 16, 1991.

151

Powers C.J., McLeskey S.W., Wellstein A., Fibroblast growth factors,

their receptors and signalling, Endocr. Rel. Cancer, 165197, 7,
2000.

152

Ornitz D.M., Xu J., Colvin J.S., McEwen D.G., MacArthur C.A., Coulier
F., et al., Receptor specificity of the fibroblast growth factor family,
J. Biol. Chem., 1529215297, 271, 1996.

153

Klagsbrun M., Folkman J., Angiogenesis In: Sporn M.B., Roberts

A.B., (Eds), Peptide growth factors and their receptors. II, Springer,
New York, 1991, pp 54986.

154

Thomson A.A., Cunha G.R., Prostatic growth and development are

regulated by FGF10, Development, 36933370, 126, 1999.

155

Shaulian E., Resnitzky D., Shifman O., Blandino G., Amsyterdan A.,
Yayon A., et al., Induction of Mdm2 and enhancement of cell survival
by bFGF, Oncogene, 27172725, 15, 1997.

156

Song S.H., Wientjes M.G., Gan Y., Au J.L.S., Fibroblast growth

factors: An epigenetic mechanism of broad spectrum resistance to
anticancer drugs, Proc. Natl. Acad. Sci. USA, 86588663, 97, 2000.

157

Cronauer M.V., Schulz W.A., Seifert H.-H., Ackermann R. and

Burchardt M., Fibroblast growth factors and their receptors in
urological cancers: basic research and clinical implications, Eur. Urol.,
309-319, 43, 2003.

158

Elkin M., Ilan N., Ishai-Michaeli R., Friedmann Y., Papo O., Pecker I.
et al., Heparanase as mediator of angiogenesis: Mode of action,
FASEB J., 16611663, 15, 2001.

159

Wu D.Q., Kan M.K., Sato G.H, Okamoto T., Sato J.D.,

Characterization and molecular cloning of a putative binding protein
for heparin-binding growth factors, J. Biol. Chem., 1677816785,
266, 1991.

160

Liu X.-H., Aigner A., Wellstein A. and Ray P.E., Up-regulation of a

fibroblast growth factor-binding protein in children with renal
diseases, Kidney Int., 17171728, 59, 2001.

161

Kornmann M., Ishiwata T., Beger H.G., Korc M., Fibroblast growth
factor-5 stimulates mitogenic signaling and is overexpressed in

-61-

2:

human pancreatic cancer: Evidence for autocrine and paracrine

actions, Oncogene 14171424, 15, 1997.
162

Auguste P., Gursel D.B., Lemiere S., Reimers D., Cuevas P., Carceller
F., Di Santo J.P., Bikfalvi A., Inhibition of fibroblast growth
factor/fibroblast growth factor receptor activity in glioma cells
impedes tumor growth by both angiogenesis-dependent and
independent mechanisms, Cancer Res., 17171726, 61, 2001.

163

Shingu K., Fujimori M., Ito K., Hama Y., Kasuga Y., Kobayashi S.,
Itoh N., Amano J., Expression of fibroblast growth factor-and
fibroblast growth factor receptor-1 in thyroid diseases: Difference
between neoplasms and hyperplastic lesions, Endocr. J., 35-43, 45,
1998.

164

Chesi M., Nardini E., Brents L.A., Schrock E., Ried T., Kuehl W.M.,
Bergsagel P.L., Frequent translocation t(4;14)(p16.3;q32.3) in
multiple myeloma is associated with increased expression and
activating mutations of .broblast growth factor receptor 3, Nat.
Genet., 260264, 16, 1997.

165

Takano S., Gately S., Neville M.E., Herblin W.F., Gross J.L.,
Engelhard H, Perricone M., Eidsvoog K., Brem S., Suramin, an
anticancer and angiosuppressive agent, inhibits endothelial cell
binding of basic fibroblast growth factor, migration, proliferation, and
induction of urokinase-type plasminogen activator, Cancer Res.,
26542660, 54, 1994.

166

Beitz J.G., Davol P., Clark J.W., Kato J., Medina M., Frackelton A.R.,
Lappi D.A., Baird A., Calabresi P., Antitumor activity of basic
fibroblast growth factor-saporin mitotoxin in vitro and in vivo,
Cancer Res., 227230, 52, 1992.

167

Mohammadi M., McMahon G., Sun L., et al, Structures of the

tyrosine kinase domain of fibroblast growth factor receptor in
complex with inhibitors, Science, 955-960, 276, 1997.

168

Martinelli G., Tosi P., Ottaviani ., Soverini S., Tura S., Molecular
therapy for multiple myeloma, Haematologica, 908-917, 86, 2001.

169

Laird A.D., Vajkoczy P., Shawver L.K., Thurnher A., Liang C,

Mohammadi M., et al., SU6668 is a potent antiangiogenic and
antitumor agent that induces regression of established tumors
Cancer Res., 41524160, 60, 2000.

170

Mohammadi M., Froum S., Hamby J. M., et al, Crystal structure of

an angiogenesis inhibitor bound to the FGF receptor tyrosine kinase
domain, EMBO J., 5896-5904,17, 1998.

-62-

3:

(1976-1985) ,
,

1 .

-,

,
.
/,

. ,

,

.

,
- (PDGFR, EGFR),
- (Src, Abl),
(G-
Ras) 2 .


3 .

-63-

3:

, ,
,

, 4 ,

.

. ,
,

5 , 6 ,
. ,

.


.

.

, . ,
,
. ,

,

-64-

3:

15. .

17
stress

-65-

3:

,
,

, (
)
.
,
,
,

.

.
(tamoxifen) (bicalutamide)

8 .

(resident nuclear proteins),

-.

1987,

Jun (v- Jun

c- Jun
),
, ,
,
. c-Jun

9 .

c-Jun

c-Jun, JNK (c-Jun Nterminal kinase)

Ser63 Ser73.

-66-

3:

(latent

cytoplasmatic

factors),

10 .

(
Ca2+) .
,
-
,
.

.
,
.
,

(Resident

nuclear

proteins)

.
, bZip

-67-

3:

, o c-Jun, JUNB, JUND, o c-Fos, o FRA,

ATFs CREB-CREM, cEBP,
ETS MAD.

.

Ras,

MAP


.

.
DNA

/.

DNA
(co-activators) .

ETS
c-Jun,
AP1.
ETS
(
) 11 .
JUN ,

- (RTKs), ,

(NRTKs)

c-Jun. ,
c-Jun

-68-

3:

,
EGF PDGF
c-Jun.

AP-1 (Jun-Fos)
AP-1 -
Jun Fos 12 . Jun Fos
(basic-region leucine
zipper domain, bZIP) bZIP
(MAF, ATF, CNC C/EBP),
DNA,
cAMP (cAMP response element, CRE)
(antioxidant response elements, ARE).
Jun-Fos 12-tetradecanoylphorbol-13-acetate (TPA), TRE. , AP-1
,
p65 NF-B, CBP (CRE-binding-protein-binding
protein)

(p300),

SMAD-3

13

-4,

Jun Fos .
AP-1 ,
, ,
,

. , , stress,
( , tumor necrosis factor-TNF,
IL-1 ), ROS DNA
( ),
14 .
-

MAPK.

15 .

,
.

-69-

3:

JNK

. ASK-1, MEKK-1, MLK
-1 JNK, 16 .


, -3 TAK-1 NF-B.
AP-1
stress JNK
p38 17 .
,
stress . -
JNK, c-Jun,

AP-1.

AP-1. ,

JNK p53, c-Myc
Bcl-2 18 .
-
JNK ,

DNA

stress

.
, JNK
- ,
,
DNA .

JNK

c-Jun. c-Jun
,

DNA 19 .

-70-

3:

16. JNK.

JNK
. , CEP-1347 20
MLKs JNK,
SP600125 21

JNK.

H
N

S
N

N NH

HO COOCH3

CEP 1347

SP600125

17. JNK.

-71-

3:

(Signal

transducers

and

activators

of

transcription,

STATs)-

JAK/STATs
STATs

22 ,

. JAK -

(JAK(pTyr)- (pTyr )-STAT(pTyr))

STATs. - (EGF,
PDGF) STATs (nn-receptor tyrosine kinases, NRTKs).
, STATs
Src . ,
G- (G-protein coupled receptors, GPCRs)
STATs,
SRC JAKs. STATs SH2

SH2 .
(importins) STATs
23 .

20
STAT.
7 STATs . , ,

(missing protein) 24 .

STAT5

(glucocorticoid

receptor,

GR),

STAT1

GR SP1
PU1.

STAT1,

3,

-72-

3:

11,23

STAT DNA

18. JAK/STATs.

STATs

(histone

CREB

acetyltransferases,

HATs)23.

STATs
.

-73-

3:

STATs,

-
SOCS (suppressor of
cytokine signalling)
STATs 25 . -
STATs
.
STATs

26

STAT5 ,
STAT3

EGF. STAT3
6,

SOCS1 27 .
STAT1 STAT3

STAT3.
STAT3
.
STAT3
DNA,
STAT3 c-Jun, CBP/p300 GR,
STAT323.
JAK
in
vivo in vitro 28 .

NF-B
(nuclear factor
B, NF-B)
29 .

-74-

3:

1 (IL-1)
- (tumor necrosis factor-, TNF-).

OH
O
O

H3CO

HCl

H3CO
ZM449829

N
N
WHI-P131

ZM39923

NH2
N

N S

PP1

TDZD

19. J/STAT.

NF-B
.
IL-1 TNF-

(inhibitor of B kinase, IB) .

IB .
NF-B p65-p50
30 .
p65 IB.

, IB,
(ubiquitylation) .
p65 .
NF-B, p50,
p100, ,

-75-

3:

(ankyrin
repeats). , p50
p65, ,
. p65

I. ,

20. NF-B.

NF-B
I, NF-

-76-

3:

B. ,
, NF-B.
NF-B

, p65.
, A20
NF-B IL-1
TNF-, NF-B 31 .

NF-B

32
(

),

REED-STERNBERG Hodgkins.

p65 p50 NF-B,

v-rel

30

. NF-B -,
v-rel
. NF-B
,
Hodgkins,
(dominant-negative)
NF-B .
,

NF-B.
I p65
p100 p50.
I

I.

NF-B ,
NF-B

NF-B

IRFs, AP1,
.

-77-

3:

WNT- (The WNT-catenin signalling pathway)

Wnt

33

. Wnt,
(frizzled proteins),
(low density lipoprotein, LDL).

G-

. Dishevelled
Drosophilla.
- GSK3
(glycogen synthetase kinase-3).
GSK3
(catenins)

34 ,

(-cadherins),

. -

(axin) adenomatous polyposis coli (APC),

34. , GSK3 APC

.
Wnt Frizzled, GSK3 ,
- -
. -
DNA DNA
TCFs/LEFs (T-cell factors or lymphocyte-enhancer factors)

(transcription-activation domain, TAD). -

-78-

TAD

3:

35

.
LEF/TCF
mRNA
Drosophilla o
WNT.
-
APC
34,36 . / -

, -
(desmoids)36.

LEF/TCF,

,
.

Varmus H.E., Oncogenes and transcriptional control, Science,

13371339, 238, 1987.

Vogt P.K., Jun, the oncoprotein, Oncogene. 23652377, 20, 2001.

Griffin J.D., Phosphatidyl inositol signaling by BCR/ABL:

Opportunities for drug development, Cancer Chemother. Pharmacol.,
S11S16, 48 (suppl 1), 2001.

Green D.R., Evan G.I., A matter of life and death, Cancer Cell, 1930, 1, 2002.

McCormick F., Cancer gene therapy: Fringe or cutting edge? Nat.

Rev. Cancer,130141, 1, 2001.

Gibbs J.B., Mechanism-based target identification and drug discovery

in cancer, Science 19691973, 287, 2000.

Committee on Developmental Toxicology, Scientific Frontiers in

Developmental Toxicology and Risk Assessment, National Academy
Press, Washington, D.C., 2000.

-79-

3:

Tilley W.D., Clarke C.L., Birrell S.N., Bruchovsky N., Hormones and
cancer: New insights, new challenges, Trends Endocrinol. Metab.,
186188, 12, 2001.

Debatin K.M., Activation of apoptosis pathways by anticancer

treatment, Toxicol. Lett., 41-48, 112/113, 2000.

10

Brivanlou A.H., Darnell J.E. Jr., Signal transduction and the control
of gene expression, Science, 813818, 295, 2002.

11

Gilliland D.G., The diverse role of the ETS family of transcription

factors in cancer, Clin. Cancer Res., 451453, 7, 2001.

12

Wagner E.F., AP-1 articles, Oncogene, 23332497, 20, 2001.

13

Chinenov Y., Kerppola T.K., Close encounters of many kinds: Fos

Jun interactions that mediate transcription regulatory specificity,
Oncogene, 24382452, 20, 2001.

14

Darnell J.E. Jr, Transcription factors as targets for cancer therapy,

Nat. Rev. Cancer, 740-749, 2, 2002.

15

Leppa S., Bohmann D., Diverse functions of JNK signaling and c-Jun
in stress response and apoptosis, Oncogene, 61586162, 18, 1999.

16

Jarpe M.B., Widmann C., Knall C., et al., Anti-apoptotic versus proapoptotic signal transduction: Checkpoints and stop signs along the
road to death, Oncogene 14751482, 17, 1998.

17

Chang L., Karin M., Mammalian MAP kinase signaling cascades,

Nature, 3740, 410, 2001.

18

Herr I., Debatin K.-M., Cellular stress response and apoptosis in

cancer therapy, Blood, 26032614, 98, 2001.

19

Pan B., Yao K.-S., Monia B.P., Dean N.M., McKay R.A., Hamilton T.C.,
ODwyer P.J., Reversal of cisplatin resistance by a c-jun antisense
oligodeoxynucleotide (ISIS 10582): Evidence for the role of
transcription factor overexpression in determining resistant
phenotype, Biochem. Pharmacol., 16991707, 63, 2002.

20

Maroney A.C., Glicksman A.N., Basma A.N., Walton K.M., Knight C.A.,
Murphy C.A., Barlet B.A., et al., Motoneuron apoptosis is blocked by
CEP-1347 (KT 7515), a novel inhibitor of the JNK signaling
pathways, J. Neurosci., 104-111, 18, 1998.

21

Bennett B.L., Sasaki D.T., Murray B.W., OLery, Sakata S.T., Xu W.,
et al, SP600125, and antrapyrazolone inhibitor of the Jun N-terminal
kinase, Proc. Natl. Acad. Sci. USA, 13681-13686, 98, 2001.

22

Levy D., Darnell J.E., Jr, STATs: Transcriptional control and biologic
impact, Nat. Rev. Mol. Cell Bio., 651662, 3, 2002.

23

McBride K.M., Banninger G., McDonald C., Reich N.C., Regulated

nuclear import of the STAT1 transcription factor by direct binding of
importin-, EMBO J., 17541763, 21, 2002.

24

Darnell J.E. Jr, STATs and gene regulation, Science, 16301635,

277, 1997.

25

Starr R., Hilton D.J., Negative regulation of the JAK/STAT pathway,

Bioassays, 4752, 21, 1999.

-80-

3:

26

Bowman T., Garcia R., Turkson J., Jove R., STATs in oncogenesis,
Oncogene, 24742488, 19, 2000.

27

Yoshikawa H. et al., SOCS-1, a negative regulator of the JAK/STAT

pathway, is silenced by ethylation in human hepatocellular carcinoma
and shows growth-suppression activity, Nat. Genet., 2935, 28,
2001.

28

Luo C., Laja P., Inhibitors of JAKs/STATs and the kinases: A possible
new cluster of drugs, Drug Discov. Today, 268-275, 9, 2004.

29

Perkins N.D., The Rel/NF-B family: Friend and foe, Trends Biochem.
Sci., 434440, 25, 2000.

30

Sen R., Baltimore D., Inducibility of kappa immunoglobulin

enhancer-binding protein NF-B by a posttranslational mechanism,
Cell, 921928, 47, 1986.

31

Song H.Y., Rothe M., Goeddel D.V., The tumor necrosis factorinducible zinc finger protein A20 interacts with TRAF1/TRAF2 and
inhibits NF-B activation, Proc. Natl. Acad. Sci. USA, 67216725,
93, 1996.

32

Rayet B., Gelinas C., Aberrant REL/NF-B genes and activity in

human cancer, Oncogene, 69386947, 18, 1999.

33

Taipale J., Beachy P.A., The Hedgehog and Wnt signaling pathways
in cancer, Nature, 349354, 411, 2001.

34

Kolligs F.T., et al., Gamma-catenin is regulated by the APC tumor

suppressor and its oncogenic activity is distinct from that of betacatenin, Genes Dev., 13191331, 14, 2000.

35

Kramps T. et al., Wnt/wingless signaling requires BCL9/leglessmediated recruitment of pygopus to the nuclear beta-catenin-TCF
complex, Cell, 4760, 109, 2002.

36

Barker N., Clevers H., Catenins, Wnt signaling and cancer,

Bioessays, 961965, 22, 2000.

-81-

4:

1990

.
,


- .



. ,

,

, ,
1 .
1953 Alma Howard
Stephen Pelc

2 .

32

DNA

, 12

DNA. ,
Howard Pelc DNA
6
8
DNA. Howard Pelc

-82-

4:

: ,
DNA , G1 ,
DNA, S- - , G2
. .


3 .
,
.
:
, ,
;
:

;

.

,
DNA
. ,
: ,
,
. ,
, .

,
G1, S G2 4 . DNA
S
. S (gap) G1

DNA. G1
G2

-83-

4:

. , G1, S, G2
. G1
(2), G2
(4) S DNA ,
2 4.

G1, DNA,
G0
,
5
G0
.

21. .

18-24 . G1
, , 6
, 12

-84-

4:

. S ,

, 6-8 .
G2 3-4 . G2
, 1

.

,


6 .


7 .

,
. G1
.
,
,
S .
R (restriction point, R)
START 7.

R G0,
R
8 .

(checkpoints)

9 .
DNA

-85-

4:

,
,
DNA

7,

10

DNA

. DNA
S ( G1-S, G1-S
checkpoint) DNA ( G2-, G2-
checkpoint) DNA
S M. ,
(spindle checkpoint),

.
(cyclin dependent kinases, CDKs) 11 ,
/
. CDKs
,

. CDKs

.
CDK .
/CDKs

-86-

12, 13 , 14

4:

CDKs
. ,
15, 16 , 17 , 18 , 19 , 20 , 21
22 .

/CDKs
.
CDKs, CDKs 1, 2, 3, 4 6

. , G1 CDK4, 6 2,
S CDK2, G2 CDK1. CDK7
23,24 .
/CDKs
D/CDK4, 6, E/CDK2,
/CDK2 /CDK1, cdc2.
D, (D1, D2 D3) CDK4, 6
G1 25 .
, D ,

26

/CDKs

/CDK2
R G1,
S 27 . /CDK2
S 28,29 .
G2 CDK1
.
/CDK1 30,31 .

32,33,34 .
(destruction box), D
PEST, (proline, P),
(glutamic acid, G), (serine, S) (threonine, T).

(ubiquitin -mediated
cyclin proteolysis) 35,36 .

-87-

4:

22. ..

CDKs
CDKs ,
. :
:

CDK.
CDK,
-
CDK.
:
CDKs

.
D G1

-88-

4:

,

. ,

.
- :

CDKs.

CDKs

CDK , CAKs (CDK-activating kinases, CAKs)

CDKs

,
.
CDKs
. CDK1
161 ( 172
CD4 160 CD2)
/CDK7, CAK.

37,38 . , Wee1 Myt1

CDK1 -15 / -14, .
Cdc25
CDK1
39 . , CAKs
- RNA
40 .
/ :
CDKs
,
CDK, CIK (CDK inhibitors, CKI)
CDK /CDK
. CDK ,

INK4

Cip/Kip 41 .

INK4

p15(INK4b), p16(NK4a), p18(NK4c)

p19(NK4d) CDK4 6
G1 .

-89-

4:

CDKs ,
D 42 .

CDK-

Cip/Kip

, p21(Waf1, Cip1), p27(Cip2)

p57(Kip2).

/CDK 43, 44 , 45 . /CDK G1

/CDK1 46 . ,
p21 DNA

(proliferating cell nuclear antigen, PCNA)

47,48

PCNA

. CKI

.
p21,
p53. p21
p53, p53
p21 49 . ,
p15 p27,
, TGF (transforming
growth factor , TGF),
50,51 .

.
,
.
Wee1 Myt1 Golgi
52,53 .
14-3-3
.
Cdc25,
14-3-3. /CDK1

14-3-3

54,55

DNA

CDKs

CDKs
24, 56 , 57 .

-90-

4:

: /CDK7/1
TFIIH.
/CDK7

C/CDK8

RNA

, /CDK9

transcription

elongation

factor

b,

P-TEFb

P-TEFb),

(positive

Tat HIV-1. CDK10

Ets2

CDK7, 8 914

: CDK5

(metabotropic

glutamate receptor) .

:
, CDKs
. , CDK5
CDK9

, CDK2 . , CDKs,

.

: CDK1, 4, 6

. ,

CDKs. CDK5 CDK11 .

CDKs

Golgi,

-
.

-91-

4:

CDKs
CDKs

.

pRb (retinoblastoma tumor suppressor gene, pRb)

D/ CDK4, 6.
G1 pRb

(histone deacetylase protein, HDAC)
E2F-1 DP-1,

S ,
, Cdc25 58, 59 , 60 .

pRb

, /CDK2
.
/CDK2 , p27,
G1/S ,

61,62

, NPAT (nuclear protein mapped to the ATM locus)

/CDK2.
NPAT G1/S,
S 63 . 1
, /CDK2,

DNA,
/CDK1 64 . CDKs
DNA (alpha
primase DNA polymerase),

DNA 65 .

CDKs

Wee 1 Cdc25 ,

(lamins),

(microtubules) (vimentin),
66, 67 , 68 , 69 .

-92-

4:

23. .

G1:
D1, D2 D3,
CDK4, 625. D
.
D/CDK4

/CDK7

70

. ,
pRb
E2F DP
-
pRb. E2F/DP ,

pRb

-93-

(HDAC)

4:

71 .

pRb E2F/DP
,
G1 S
DNA. pRb
D/CDK4, 6 HDAC

CDK2.

pRb

E2F,
.
/CDK2 pRb
72 .
pRb
E2F/DP,

E2F

, E2F .


( D)
(
)
S: S
DNA,
, 17.

/CDK2 E2Fs
DP-1 ,
DNA 73 . ,
/CDK2 cdc6,
DNA,

74

DNA . CDK2,
CDK1.
/CDK1,
75 .

-94-

4:

G2: S,
/CDK1
S G2

76 .

CDK1
(Tyr15, Thr14)
Wee1 Myt1

, DNA
77,78 .

csdc25, CDK124.
,

/ CDK1 79 . ,
/CDK1
,
DNA 80 .

,
81 .

&
4

82 .

4a

: p15(INK4b) p16(NK4a)
(9p21), p18(NK4c) p19(NK4d) 83 .
p16 CDK4, 6,
CDK4 in vitro ( 4a,
CDK4, inhibitor of CDK4). O 4a
(9p21), , p15 p16,
(alternative reading frame,

-95-

4:

ARF), p14(ARF) 132 84 .

p14(ARF) p16.
INK4a CDK4 6
D

85 . INK4a CDK4 6,
CIP/KIP,
CDK2 INK4a.

G1. INK4a

pRb.

To

60%

p16(NK4a) pRb 86 .

p16

ARF,

nullizygous
87

ARF

,
ARF
p53,
p21. p53
,
88 .
p53
. DNA,
p53
89 . p53 ,
p21, Mdm2 Bax 90 .
p21, CKI
,
DNA 91 . H Mdm2
p53:
p53

92

. p53

-96-

4:

ARF ,

p53

Mdm2 93 .

DNA, p53
Bax, Fas
stress, ,
89, 94 , 95 , 96 .
DNA (ataxia-telangiectasia-mutaded, ATM)
ataxia and rad3 related, ATR).
p53 DNA
p21,
G1/S 97 . DNA (DNA protein kinase, DNA-PK),
DNA
ATM ATR 98 .
p16

99,100 .

Cip/Kip

inhibitor/protein)

Cip/Kip

(CDK

interacting

protein

Kinase

p21(Waf1, Cip1),

p27(Cip2) p57(Kip2)45,101 .
,
, CDKs 102 .
p21 CDK2.
Waf1,
p53141. G1,
p21
/CDK2. p27
, ,
TGF 103 .
Cip/Kip CDKs
D, E 104 .
105 . p21 p27
/CDK2 .

-97-

4:

Cip/Kip

106

G1

. CDKs D

p21 p27, 107 . ,

p21 p27
D/CDKs. , Cip/Kip
D CDK4,
D/CDK4, 6 108 .
, , , Cip/Kip
CDK4 6 CDK2.
p21/p27
CDK. ,
p21

p21
D1/CDK4.
:
/CDK ( Cip/Kip),
CDKs (cdc25A)
(E2F)103. , Kaposi
(Kaposis

sarcoma

herpesvirus)

Cip/Kip, ,

p21 109,110 .

/CDKs
.
E2F /CDK2 111 .
CDK2
Cip/Kip
CDKs. , p21 p27
DNA,
.
p21

p27 . ,

p21

-98-

4:

DNA,

/CDK1 G2 112 .
p27 .
p27 ,
113 .
Cip/Kip
. p21 ,
NF-, STAT3, Myc, C/EBP
E2F 114, 115 , 116 ,
,
DNA , ,
B1 CDK1 117 . , p21
CBP/p300 118 . p21 DNA

119

CDK2,
. E2F, Myc STAT3

. , p27
AP-1 JAB1 120 .

p27

/ .
p27 187
/ CDK2 p27 121 .
p27 SCF
(Skp2) .

Lundberg A.S. and Weinberg R.A., Control of the cell cycle and
apoptosis, Eur. J. Cancer, 1886-1894, 35, 1999.

-99-

4:

Howard A., & Pelc S., Synthesis of deoxyribonucleic acid in normal

and irradiated ceils and its relation to chromosome breakage,
Heredity, 261273, 6, 1953.

Nurse P., Universal control mechanism regulating onset of M-phase,

Nature, 503508, 344, 1990.

Norbury C., Nurse P., Animal cell cycles and their control, Annu.
Rev. Biochem., 441, 61, 1992.

Hunter T., Pines J., Cyclins and cancer II: Cyclin D and CDK
inhibitors come of age. Cell, 573-583, 79, 1994.

Brooks G. and La Thangue N.B., The cell cycle and drug discovery:
The promise and the hope, Drug Discov. Today, 455-464, 4, 1999.

Hartwell L., Introduction to cell cycle controls, In: Hutchison C., and
Glover D.M., (Eds), Cell Cycle Control, IRL Press, New York, 1995, pp.
115.

Pardee A.B., A restriction point for control of normal animal cell

proliferation, Proc. Natl. Acad. Sci. USA , 1286-1290, 71, 1974.

Hartwell L.H., Weinert T.A., Checkpoints: Controls that ensure the

order of cell cycle events, Science, 629, 246, 1989.

10

Nurse P., Chekpoint pathways come of age, Cell, 865867, 91,

1997.

11

Pines J., Cyclins and cyclin-dependent kinases:

variations, Ad. Cancer Res., 181-212, 66, 1995.

12

MacLachlan T.K., Sang N., Giordano A., Cyclins, cyclin-dependent

kinases and Cdk inhibitors: Implications in cell cycle control and
cancer, Crit. Rev. Eukar. Gene, 127156, 5, 1995.

13

Peng J., Zhu Y., Milton J.T., Price D.H., Identification of multiple
cyclin subunits of human P-TEFb, Genes Dev., 755-762, 12, 1998.

14

Edwards M.C., Wong C., Elledge S.J., Human cyclin K, a novel RNA
polymerase II-associated cyclin possessing both carboxy-terminal
domain kinase and Cdk-activating kinase activity, Mol. Cell. Biol.,
4291-4300, 18, 1998.

15

Udvardy A., The role of controlled proteolysis

regulation, Eur. J. Biochem., 307-313, 240, 1996.

16

Diehl J.A., Zindy F., Sherr C.J., Inhibition of cyclin D1

phosphorylation on threonine-286 prevents its rapid degradation via
the ubiquitin-proteasome pathway, Genes Dev., 957-972, 11, 1997.

17

Clurman B.E., Sheaff R.J., Thress K., Groudine M., Roberts J.M.,
Turnover of cyclin E by the ubiquitin-proteasome pathway is
regulated by cdk2 binding and cyclin phosphorylation, Genes Dev.,
1979-1990, 10, 1996.

18

Won K.A., Reed S.I., Activation of cyclin E/CDK2 is coupled to sitespecific autophosphorylation and ubiquitin-dependent degradation of
cyclin E, EMBO J., 4182-4193, 15, 1996.

19

Sudakin V., Ganoth D., Dahan A., Heller H., Hershko J., Luca F.C.,
Ruderman J.V., Hershko A., The cyclosome, a large complex

-100-

Theme

in

and

cell-cycle

4:

containing cyclin-selective ubiquitin ligase activity, targets cyclins for

destruction at the end of mitosis, Mol. Biol. Cell, 185-197, 6, 1995.
20

Klotzbucher A., Stewart E., Harrison D., Hunt T., The 'destruction
box' of cyclin A allows B-type cyclins to be ubiquitinated, but not
efficiently destroyed, EMBO J., 3053-3064, 15, 1996.

21

Diehl J.A., Cheng M., Roussel M.F., Sherr C.J., Glycogen synthase
kinase-3 regulates cyclin D1 proteolysis and subcellular localization,
Genes Dev., 3499-3511, 12, 1998.

22

Evans T., Rosenthal E.T., Youngblom J., Distel D., Hunt T. Cyclin: A
protein specied by maternal mRNA in sea urchin eggs that is
destroyed at each cleavage division, Cell, 389-396, 33, 1983.

23

Harper J.W., Adams P.D., Cyclin-Dependent Kinases, Chem. Rev.,

2511-2526, 101, 2001.

24

Morgan D.O., Cyclin-dependent kinases: Engines, clocks, and

microprocessors, Annu. Rev. Cell Dev. Biol., 261-291, 13, 1997.

25

Sherr C.J., G1 phase progression: Cycling on cue, Cell, 551-555,

79, 1994

26

Assoian R.K., Zhu X., Cell anchorage and the cytoskeleton as

partners in growth factor dependent cell cycle progression, Curr.
Opin. Cell Biol. 93-98, 9, 1997.

27

Ohtsubo M., Theodoras A.M., Schumacher J., Roberts J.M., Pagano

M., Human cyclin E, a nuclear protein essential for the G1-to-S
phase transition, Mol. Cell Biol., 2612-2624, 15, 1995.

28

Girard F., Strausfeld U., Fernandez A., Lamb N.J., Cyclin A is

required for the onset of DNA replication in mammalian fibroblasts,
Cell, 1169-1179, 67, 1991.

29

Walker D.H., Maller J.L., Role for cyclin A in the dependence of

mitosis on completion of DNA replication, Nature, 314-317, 354,
1991.

30

King R.W., Jackson P.K., Kirschner M.W., Mitosis in transition, Cell,

563-571, 79, 1994.

31

Arellano M., Moreno S., Regulation of CDK/cyclin complexes during

the cell cycle, Int. J. Biochem. Cell Biol., 559-573, 29, 1997.

32

Peng J., Marshall N.F., Price D.H., Identification of a cyclin subunit

required for the function of Drosophila P-TEFb, J. Biol. Chem.,
13855-13860, 273, 1998.

33

Okamoto K., Beach D., Cyclin G is a transcriptional target of the p53

tumor suppressor protein, EMBO J., 4816-4822, 13, 1994.

34

Rickert P., Seghezzi W., Shanahan F., Cho H., Lees E., Cyclin
C/CDK8 is a novel CTD kinase associated with RNA polymerase II,
Oncogene, 2631-2640, 12, 1996.

35

Glotzer M., Murray A.W., Kirschner M.W., Cyclin is degraded by the

ubiquitin pathway, Nature, 132-138, 349, 1991.

36

Rechsteiner M., Rogers S.W., PEST sequences and regulation by

proteolysis, Trends Biochem. Sci., 267-271, 21, 1996.

-101-

4:

37

Jeffrey P.D., Russo A.A., Polyak K., Gibbs E., Hurwitz J., Massague J.,
Pavletich N.P., Mechanism of CDK activation revealed by the
structure of a cyclinA-CDK2 complex, Nature, 313-320, 376, 1995.

38

Paulovich A.G., Hartwell L.H., A checkpoint regulates the rate of

progression through S phase in S. cerevisiae in response to DNA
damage, Cell, 841-847, 82, 1995.

39

Lew D.J., Kornbluth S., Regulatory roles of cyclin-dependent kinase

phosphorylation in cell cycle control, Curr. Opin. Cell Biol., 795-804,
8, 1996.

40

Fisher R.P., Morgan D.O., CAK in TFIIH: Crucial connection or

confounding coincidence?, Biochim. Biophys. Acta, 7-10, 1288,
1996.

41

Sherr C.J., Roberts J.M., Inhibitors of mammalian G1 cyclindependent kinases, Genes Dev., 1149-1163, 9, 1995.

42

Carnero A., Hannon G.J., The INK4 family of CDK inhibitors, Curr.
Top. Microbiol. Immunol., 43-55, 227, 1998.

43

Polyak K., Lee M.H., Erdjument B.H., Koff A., Roberts J.M., Tempst
P., Massague J., Cloning of p27Kip1, a cyclin-dependent kinase
inhibitor and a potential mediator of extracellular antimitogenic
signals, Cell, 59-66, 78, 1994.

44

Harper J.W., Elledge S.J., Keyomarsi K., Dynlacht B., Tsai L.H.,
Zhang P., Dobrowolski S., Bai C., Connell C.L., Swindell E., et al.,
Inhibition of cyclin-dependent kinases by p21, Mol. Biol. Cell, 387400, 6, 1995.

45

Lee M.H., Reynisdottir I., Massague J., Cloning of p57KIP2, a cyclindependent kinase inhibitor with unique domain structure and tissue
distribution, Genes Dev., 639-649, 9, 1995.

46

Hengst L., Reed S.I., Inhibitors of the Cip /Kip family, Curr. Top.
Microbiol. Immunol., 25-41, 227, 1998.

47

Pan Z.Q., Reardon J.T., Li L., Flores R.H., Legerski R., Sancar A.,
Hurwitz J., Inhibition of nucleotide excision repair by the cyclindependent kinase inhibitor p21, J. Biol. Chem.,22008-22016, 270,
1995.

48

Waga S., Li R., Stillman B., p53-induced p21 controls DNA

replication, Leukemia, 321-323, 11, 1997.

49

l Deiry W.S., Tokino T., Velculescu V.E., Levy D.B., Parsons R., Trent
J.M., Lin D., Mercer W.E., Kinzler K.W., Vogelstein B., WAF1, a
potential mediator of p53 tumor suppression, Cell, 817-825, 75,
1993.

50

Hannon G.J., Beach D., p15INK4B is a potential effector of TGF-binduced cell cycle arrest, Nature, 257-261, 371, 1994.

51

Reynisdottir I., Polyak K., Iavarone Massague J., Kip/cip and INK4
CDK inhibitors co-operate to induce cell cycle arrest in response to
TGF-b, Genes Dev., 1831-1845, 9, 1995.

-102-

4:

52

Heald R, McLoughlin M, McKeon F, Human wee1 maintains mitotic

timing by protecting the nucleus from cytoplasmically activated Cdc2
kinase, Cell, 463-474, 74, 1993.

53

Liu F., Stanton J.J., Wu Z., Piwnica W.H., The human Myt1 kinase
preferentially phosphorylates Cdc2 on threonine 14 and localizes to
the endoplasmic reticulum and Golgi complex, Mol. Cell Biol., 571583, 17, 1997.

54

Peng C.Y., Graves P.R., Thoma R.S., Wu Z., Shaw A.S., Piwnica W.H.,
Mitotic and G2 checkpoint control: Regulation of 143-3 protein
binding by phosphorylation of Cdc25C on serine-216, Science, 15011505, 277, 1997.

55

Yang J., Winkler K., Yoshida M., Kornbluth S., Maintenance of G2

arrest in the Xenopus oocyte: A role for 143-3 mediated inhibition of
Cdc25 nuclear import, EMBO J., 2174-2183, 18, 1999.

56

Pavletich N.P., Mechanisms of cyclin-dependent kinase regulation:

structures of cdks, their cyclin activators, and Cip and INK4
inhibitors, J. Mol. Biol., 821-828, 287, 1999.

57

Dhavan R. and Tsai L.-H., A decade of CDK5, Nat. Rev. Mol. Cell
Biol., 749-759, 2, 2001.

58

Buchkovich K, Duffy L.A., Harlow E., The retinoblastoma protein is

phosphorylated during specific phases of the cell cycle, Cell, 10971105, 58, 1989.

59

Kato J., Matsushime H., Hiebert S.W., Ewen M.E., Sherr C.J., Direct
binding of cyclin D to the retinoblastoma gene product (pRb) and pRb
phosphorylation by the cyclin d-dependent kinase CDK4, Genes
Dev., 331-342, 7, 1993.

60

Brehm A., Miska E.A., McCance D.J., Reid J.L., Bannister A.J.,
Kouzarides T., Retinoblastoma protein recruits histone deacetylase
to repress transcription, Nature, 597-601, 391, 1998.

61

Hinds P.W., Mittnacht S., Dulic V., Arnold A., Reed S.I., Weinberg
R.A., Regulation of retinoblastoma protein functions by ectopic
expression of human cyclins, Cell, 993-1006, 70, 1992.

62

Montagnoli A., Fiore F., Eytan E., Carrano A.C., Draetta G.F., Hershko
A., Pagano M., Ubiquitination of p27 is regulated by CDK-dependent
phosphorylation and trimeric complex formation, Genes Dev., 11811189, 13, 1999.

63

Zhao J., Kennedy B.K., Lawrence B.D., Barbie D.A., Matera A.G.,
Fletcher J.A., Harlow E., NPAT links cyclin E-Cdk2 to the regulation
of replication-dependent histone gene transcription, Genes Dev.,
2283-2297, 14, 2000.

64

Bradbury E.M., Inglis R.J., Matthews H.R., Control of cell division by

very lysine rich histone (F1) phosphorylation, Nature, 257-261, 247,
1974.

65

Voitenleitner C., Fanning E., Nasheuer H.P., Phosphorylation of DNA

polymerase alpha-primase by cyclin A-dependent kinases regulates
initiation of DNA replication in vitro, Oncogene, 1611-1615, 14,
1997.

-103-

4:

66

Heald R., McKeon F., Mutations of phosphorylation sites in lamin A

that prevent nuclear lamina disassembly in mitosis, Cell, 579-589,
61, 1990.

67

Courvalin J.C., Segil N., Blobel G., Worman H.J., The lamin B
receptor of the inner nuclear membrane undergoes mitosis-specific
phosphorylation and is a substrate for p34cdc2-type protein kinase,
J. Biol. Chem., 19035-19038, 267, 1992.

68

Hoffmann I., Clarke P.R., Marcote M.J., Karsenti E., Draetta G.,
Phosphorylation and activation of human cdc25-C by cdc2cyclin B
and its involvement in the self-amplification of MPF at mitosis, EMBO
J., 53-63, 12, 1993.

69

Blangy A., Lane H.A., dHerin P., Harper M., Kress M., Nigg E.A.,
Phosphorylation by p34cdc2 regulates spindle association of human
Eg5, a kinesin-related motor essential for bipolar spindle formation in
vivo, Cell, 1159-1169, 83, 1995.

70

Kaldis P., The cdk-activating kinase (CAK).

mammals, Cell. Mol. Life Sci., 284-296, 55, 1999.

71

Ferreira R., Naguibneva I., Mathieu M.S. , Ait-Si-Ali, Robin P.,

Pritchard L.L., Harel-Bellan A., Cell cycle-dependent recruitment of
HDAC-1 correlates with deacetylation of histone H4 on an Rb-E2F
target promoter, EMBO Rep., 794-799, 2, 2001.

72

Ezhevsky S.A., Ho A., Becker-Hapak M., Davis P.K., Dowdy S.F.,

Differential regulation of retinoblastoma tumor suppressor protein by
G(1) cyclin-dependent kinase complexes in vivo, Mol. Cell. Biol.,
4773-4784, 21, 2001.

73

Xu M., Sheppard K.A., Peng C.Y., Yee A.S., Piwnica-Worms H.,

Cyclin A/CDK2 binds directly to E2F-1 and inhibits the DNA-binding
activity of E2F-1/DP-1 by phosphorylation, Mol. Cell. Biol., 84208431, 14, 1994.

74

Petersen B.O., Lukas J., Sorensen C.S., Bartek J., Helin K.,
Phosphorylation of mammalian CDC6 by cyclin A/CDK2 regulates its
subcellular localization, EMBO J., 396-410, 18, 1999.

75

Santaguida M., Ding Q., Berube G., Truscott M., Whyte P., Nepveu A.,
Phosphorylation of the CCAAT displacement protein (CDP)/Cux
transcription factor by cyclin A-Cdk1 modulates its DNA binding
activity in G2, J. Biol. Chem., 45780-45790, 276, 2001.

76

Kishimoto T., Okumura E., In vivo regulation of the entry into Mphase: Initial activation and nuclear translocation of cyclin B/Cdc2,
Prog. Cell Cycle Res., 241-249, 3, 1997.

77

McGowan C.H., Russell P., Human Wee1 kinase inhibits cell division
by phosphorylating p34cdc2 exclusively on Tyr15, EMBO J., 75-85,
12, 1993.

78

Mueller P.R., Coleman T.R., Kumagai A., Dunphy W.G., Myt1: A

membrane-associated inhibitory kinase that phosphorylates Cdc2 on
both threonine-14 and tyrosine-15, Science, 86-90, 270, 1995.

79

Smits V.A., Medema R.H., Checking out the G2/M transition,

Biochim. Biophys. Acta, 1-12, 1519, 2001.

-104-

From

yeast

to

4:

80

Papst P.J., Sugiyama H., Nagasawa M., Lucas J.J., Maller J.L., Terada
N., Cdc2-cyclin B phosphorylates p70 S6 kinase on Ser411 at
mitosis, J. Biol. Chem., 15077-15084, 273, 1998.

81

Cerutti L., Simanis V., Controlling the end of the cell cycle, Curr.
Opin. Genet. Dev., 65-69, 10, 2000.

82

Serrano M., Hannon G.J., Beach D., A new regulatory motif in cellcycle control causing specific inhibition of cyclin D/CDK4, Nature,
704-707, 366, 1993.

83

Chan F.K., Zhang J., Cheng L., Shapiro D.N., Winoto A.,
Identification of human and mouse p19, a novel CDK4 and CDK6
inhibitor with homology to p16ink4, Mol. Cell. Biol., 2682-2688, 15,
1995.

84

Quelle D.E., Zindy F., Ashmun R.A., Sherr C.J., Alternative reading
frames of the INK4a tumor suppressor gene encode two unrelated
proteins capable of inducing cell cycle arrest, Cell, 993-1000, 83,
1995.

85

Reynisdottir I., Massague J., The subcellular locations of p15Ink4b

and p27Kip1 coordinate their inhibitory interactions with cdk4 and
cdk2, Genes Dev., 492-503, 11, 1997.

86

Malumbres M., Barbacid M., Milestones in cell division: To cycle or

not to cycle: A critical decision in cancer, Nat. Rev. Cancer, 222-231,
1, 2001.

87

Kamijo T., Zindy F, Roussel M.F., et al., Tumour suppression at the

mouse INK4a locus mediated by the alternative reading frame
product of p19ARF, Cell, 649-659, 91, 1997.

88

Sherr C.J., Tumor surveillance via the ARF-p53 pathway, Genes

Dev., 2984-2991, 12, 1998.

89

Chen X., Ko L.J., Jayaraman L., Prives C., p53 levels, functional
domains, and DNA damage determine the extent of the apoptotic
response of tumor cells, Genes Dev., 2438-2451, 10, 1996.

90

Agarwal M.L., Taylor W.R., Chernov M.V., Chernova O.B., Stark G.R.,
The p53 network, J. Biol. Chem., 1-4, 273,, 1998.

91

Ko L.J., Prives C., p53: Puzzle and paradigm, Genes Dev., 10541072, 10, 1996.

92

Oren M., Regulation of the p53 tumor suppressor protein, J. Biol.

Chem., 36031-36034, 274, 1999.

93

Zhang Y., Xiong Y., Yarbrough W.G., ARF promotes MDM2

degradation and stabilizes p53: ARF-INK4a locus deletion impairs
both the Rb and p53 tumor suppression pathways, Cell, 725-734,
92, 1998.

94

Owen-Schaub L.B., Zhang .W, Cusack J.C., Angelo L.S., Santee S.M.,
Fujiwara T., Roth J.A., Deisseroth A.B., Zhang W.W., Kruzel E.A.,
Wild-type human p53 and a temperature-sensitive mutant induce
Fas/APO-1 expression, Mol. Cell Biol., 3032-3040, 15, 1995.

95

Polyak K., Xia Y., Zweier J.L., Kinzler K.W., Vogelstein B., A model
for p53-induced apoptosis, Nature, 300-305, 389, 1997.

-105-

4:

96

Gottlieb T.M., Oren M., p53 and apoptosis, Semin. Cancer Biol.,
359-368, 8, 1998.

97

Siliciano J.D., Canman C.E., Taya Y., Sakaguchi K., Appella E., Kastan
M.B., DNA damage induces phosphoryl-ation of the amino terminus
of p53, Genes Dev., 3471-3481, 11, 1997.

98

Durocher D., Jackson S.P., DNA-PK, ATM and ATR as sensors of DNA
damage: variations on a theme?, Curr. Opin. Cell Biol., 225-231, 13,
2001.

99

Krimpenfort P., Quon K.C., Mooi W.J., Loonstra A., Berns A., Loss of
p16Ink4a confers susceptibility to metastatic melanoma in mice,
Nature, 83-86, 413, 2001.

100

Sharpless N.E., Bardeesy N., Lee K.-H., et al., Loss of p16Ink4a with
retention of p19Arf predisposes mice to tumourigenesis, Nature, 8691, 413, 2001.

101

Matsuoka S., Edwards M.C., Bai C., Parker S., Zhang P., Baldini A.,
Harper J.W., Elledge S.J., p57KIP2, a structurally distinct member of
the p21CIP1 Cdk inhibitor family, is a candidate tumor suppressor
gene, Genes Dev., 650-662, 9, 1995.

102

Vidal A, Koff A., Cell-cycle inhibitors: three families united by a

common cause, Gene, 1-15, 247, 2000.

103

Swanton C., Cell-cycle targeted therapies, Lancet Oncol., 27-36, 5,

2004.

104

Zhang H., Hannon G.J., Beach D., p21-Containing cyclin kinases

exist in both active and inactive states, Genes Dev., 1750-1758, 8,
1994.

105

Cheng M., Olivier P., Diehl J.A., Fero M., Roussel M.F., Roberts J.M.,
Sherr C.J., The p21Cip1 and p27Kip1 CDK 'inhibitors' are essential
activators of cyclin D-dependent kinases in murine fibroblasts, EMBO
J., 1571-1583, 18, 1999.

106

Russo A.A., Jeffrey P.D., Patten A.K., Massague J., Pavletich N.P.,
Crystal structure of the p27Kip1 cyclin-dependent-kinase inhibitor
bound to the cyclin A-Cdk2 complex, Nature, 325-331, 382, 1996.

107

Blain S.W., Montalvo E., Massague J., Differential interaction of the

cyclin-dependent kinase (Cdk) inhibitor p27Kip1 with cyclin A-Cdk2
and cyclin D2-Cdk4, J.Biol.Chem., 25863-25872, 272, 1997.

108

Sherr C.J., Roberts J.M., CDK inhibitors: Positive and negative

regulators of G1-phase progression, Genes Dev., 1501-1512, 13,
1999.

109

Card G.L., Knowles P., Laman H., et al., Crystal structure of a

gamma-herpesvirus cyclin-cdk complex, EMBO J., 2877-2788, 19,
2000.

110

Swanton C, Mann DJ, Fleckenstein B, et al., Viral cyclin/cdk6

complexes evade inhibition by cdk inhibitory proteins, Nature, 184187, 390, 1997.

-106-

4:

111

Chen Y.-N., Sharma S., Ramsey T., et al., Selective killing of

transformed cells by cyclin/cyclin-dependent kinase 2 antagonists,
Proc. Natl. Acad. Sci. USA, 4325-4329, 96, 1999.

112

Bunz F. et al., Requirement for p53 and p21 to sustain G2 arrest

after DNA damage, Science, 1497-1501, 282, 1998.

113

Philipp-Staheli J. et al., p27(Kip1): Regulation and function of a

haploinsufficient tumor suppressor and its misregulation in cancer,
Exp. Cell Res., 148-168, 264, 2001.

114

Kitaura H. et al., Reciprocal regulation via protein-protein interaction

between c-Myc and p21(cip1/waf1/sdi1) in DNA replication and
transcription, J. Biol. Chem., 10477-10483, 275, 2000.

115

Coqueret O., and Gascan, H., Functional interaction of STAT3

transcription factor with the cell cycle inhibitor p21WAF1/CIP1/SDI1,
J. Biol. Chem., 1879418800, 275, 2000.

116

Harris T.E. et al., CCAAT/enhancer-binding protein-alpha cooperates

with p21 to inhibit cyclin-dependent kinase-2 activity and induces
growth arrest independent of DNA binding, J. Biol. Chem., 29200
29209, 276, 2001.

117

Chang B.D. et al., Effects of p21Waf1/Cip1/Sdi1 on cellular gene

expression: Implications for carcinogenesis, senescence, and agerelated diseases, Proc. Natl. Acad. Sci. USA., 42914296, 97, 2000.

118

Snowden A.W. et al., A novel transcriptional repression domain

mediates p21(WAF1/CIP1) induction of p300 transactivation, Mol.
Cell. Biol., 26762686, 20, 2000.

119

Delavaine L. and La Thangue N.B., Control of E2F activity by

p21Waf1/Cip1, Oncogene 53815392, 18, 1999.

120

Chamovitz D.A. and Segal D., JAB1/CSN5 and the COP9

signalosome. A complex situation, EMBO Rep., 96101, 2, 2001.

121

Sheaff R., Groudine M., Gordon M., et al., Cdk2 is a regulator of

p27kip1, Genes Dev., 146478, 11, 1997.

-107-

4:

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-113-

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-114-

5: &

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1990 DNA,
, 62 .
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-115-

4:

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-116-

5: &

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-117-

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Chk1 Chk2 71 . -
p53, Mdm2
p53,
DNA p53.
p53 -
Pin1, p53

p53

Mdm2 72 .

p53

, DNA245.
p53
DNA 73,74 . T

p14(ARF),

p14(ARF)

Mdm2 . p14(ARF)
,
Mdm2, p53

. Mdm2, p53

75 .
p53
,

252. ,
p53
, ,
76 . ,
p53 ,

(nuclear

bodies,

-118-

NBs)

5: &

(promyelocytic leukemia protein, PML)

Rad50/Rad51 77 .

p53.
DNA , SV40, human pappiloma virus
78 .
,
pRb
E2F, E2F-1.
E2F-1

p14(ARF),
p53, Mdm2 p53.

. ,
p53,
.
p53

.
,
ATM, Chk2 p14(ARF),
AT
(ataxia telangiectasia related, ATR) 68.

p53
69.

stress

, p53,
,
.

-119-

4:

26. p53.

p53
p53
DNA
. p53 DNA,
, p53
p53
,
p53
.
p53 :
.
p53
p21 CDKs, G1
S G2 , Reprimo
G2 79 . ,
14-3-3,

-120-

5: &

1/CDK1
G2 80,81 .
.
82 .
Bax, ,
Bcl-2
p53
Bax 83 . , NOXA ( ),
P53AIP1, PUMA (p53 Upregulated Modulator of Apoptosis),
PRSS25 ( HTRA2),

64,84

p53

PAC1,

p53
,
TNF Fas. , p53
,

c,
SMAC (second mitochondria-derived activator of caspases),
AIF (apoptosis-inducing facor)
G 85 .
.


, .
p53
DNA

86,87 .

(rebonucleotide reductase) p53

DNA,
p53 88 .
.
p53
82,84.

-121-

4:

p53
.
p53 DNA
, p53

.
p53
p53
. p53
.
,

p53
.
p53 89 ,
90 .
, p53
91 . p53

Mdm2 , , ,
92,93 .

p53,

.
, p53

94 , p53
. p53

95,96 . p53

p53
stress -

-122-

5: &

p53
stress 97 .

Sherr C.J., Cancer cell cycles, Science, 1672-1677, 274, 1996.

McDonald E.R. III, el Deiry W.S., Cell cycle control as a basis for
cancer drug development, Int. J. Oncol., 871-886, 16, 2000.

Wolfel T., Hauer M., Schneider J., Serrano M., Wolfel C., Klehmann
H.E., De Plaen E., Hankeln T., Meyerzum-Buschenfelde K.H., Beach
D., A p16INK4a-insensitive CDK4 mutant targeted by cytolytic T
lymphocytes in a human melanoma, Science, 1281-1284, 269,
1995.

Easton J., Wei T., Lahti J.M., Kidd V.J., Disruption of the cyclin
D/cyclin-dependent kinase/INK4/retinoblastoma protein regulatory
pathway in human neuroblastoma, Cancer Res., 26242632, 58,
1998.

Kim J.H., Kang M.J., Park C.U., Kwak H.J., Hwang Y., Koh G.Y.,
Amplified CDK2 and cdc2 activities in primary colorectal carcinoma,
Cancer, 546-553, 85, 1999.

Heichman, K.A. and Roberts, J.M., Rules to replicate by, Cell, 557562, 79, 1994.

King, R.W., Jackson, P.K. and Kirschner, M.W., Mitosis in transition,

Cell, 563-571, 79, 1994.

Hunter, T. and Pines, J., Cyclins and cancer. II: Cyclin D and CDK
inhibitors come of age, Cell, 573-582, 79, 1994.

Weisenburger D.D., Sanger W.G., Armitage J.O., Purtilo D.T.,

Intermediate lymphocytic lymphoma: Immunophenotypic and
cytogenetic findings, Blood, 1617-1621, 69, 1987.

10

Weinstein I.B., Begemann M., Zhou P., Han E.K.-H., Sgambato A.,
Doki Y., Arber N., Ciaparrone M. and Yamamoto H., Disorders in cell
circuitry associated with multistage carcinogenesis: Exploitable
targets for cancer prevention and therapy, Clin. Cancer Res., 26962702, 3, 1997

11

Han E.K.-H., Rubin M.A., Lim J.T., Arber N., Xing W.-Q. and
Weinstein, I.B., Cyclin D1 expression in human prostate cell lines
and primary tumors, The Prostate, 95-101, 35, 1998.

12

Malumbres M. and Barbacid M., To cycle or not to cycle: A critical

decision in cancer, Nat. Rev. Cancer, 222-31, 3, 2001.

13

Dobashi Y., Shoji M., Jiang S.X., Kobayashi M., Kawakubo Y., Kameya
T., Active cyclin A-CDK2 complex, a possible critical factor for cell
proliferation in human primary lung carcinomas, Am. J. Pathol., 963972, 153, 1998.

-123-

4:

14

Draetta G., Eckstein J., Cdc25 Protein phosphatases in

proliferation, Biochim. Biophys. Acta, M53-M63, 1332, 1997.

15

Nilsson I., Hoffmann I., Cell cycle regulation by the Cdc25

phosphatase family, Prog. Cell Cycle Res., 107-114, 4, 2000.

16

Galaktionov K., Chen X., Beach D., Cdc25 cell-cycle phosphatase as

a target of c-myc, Nature, 511-517, 382, 1996.

17

Galaktionov K., Jessus C., Beach D., Raf1 interaction with Cdc25
phosphatase ties mitogenic signal transduction to cell cycle
activation, Genes Dev., 1046-1058, 9, 1995.

18

Kamb A., Cyclin-dependent kinase inhibitors and human cancer,

Curr. Top. Microbiol. Immunol., 139-148, 227, 1998.

19

Krimpenfort P., Quon K.C., Mooi W.J., Loonstra A., Berns A., Loss of
p16Ink4a confers susceptibility to metastatic melanoma in mice,
Nature, 83-86, 413, 2001.

20

Ruas M., Peters G., p16ink4a/CDKN2A tumour suppressor and its

relatives, BBA Rev. Cancer, F115F117, 1378, 1998.

21

Harper J.W., Elledge S.J., Cdk inhibitors in development and cancer,

Curr. Opin. Genet. Dev., 56-64, 6, 1996.

22

Rocco J.W. and Sindransky D., p16(MTS-1/CDKN2/INK4a) in cancer

progression, Exp. Cell Res., 42-55, 264, 2001.

23

Chim C.S.M., Liang R., Tam C.Y., and Kwong Y.L., Methylation of
p15 and p16 genes in acute promyelocytic leukemia: Potential
diagnostic and prognostic significance, J. Clin. Oncol., 2033-2040,
19, 2001.

24

Catzavelos C., Bhattacharya N., Ung Y.C., Wilson J.A., Roncari L. and
Sandhu C., Decreased levels of the cell cycle inhibitor p27Kip1
protein: Prognostic implications in primary breast cancer, Nat. Med.,
227-230, 3, 1997.

25

Cordon-Cardo C., Koff A., Drobnjak M., Capodieci P., Osman I., and
Millard S.S., Distinct altered patterns of p27KIP1 gene expression in
benign prostatic hyperplasia and prostatic carcinoma, J. Natl. Cancer
Inst., 1284-1291, 90, 1998.

26

Lapointe J., Lachance Y., Labrie Y., Labrie C., A p18 mutant
defective in CDK6 binding in human breast cancer cells, Cancer Res.,
45864589, 56, 1996.

27

Loda M., Cukor B., Tam S.W., Lavin P., Fiorentino M., Draetta G.F.,
Jessup J.M., Pagano M., Increased proteasome-dependent
degradation of the cyclin-dependent kinase inhibitor p27 in
aggressive colorectal carcinomas, Nat. Med., 231-234, 3, 1997.

28

Deng C., Zhang P., Harper J.W., Elledge S.J., Leder P., Mice lacking
p21CIP1/WAF1 undergo normal development, but are defective in G1
checkpoint control, Cell , 675-684, 82, 1995.

29

Weinberg R.A, The retinoblastoma protein and cell cycle control,

Cell, 323-330, 81, 1995.

30

Mulligan G., Jacks T., The retinoblastoma gene family: Cousins with
overlapping interests, Trends Genet., 223-229, 14, 1998.

-124-

cell

5: &

31

Adams, P.D., Regulation of the retinoblastoma tumor suppressor

protein by cyclin/cdks, BBA Rev. Cancer, M123-M133, 1471, 2001.

32

Goodrich D.W., Lee W.H., Molecular characterization of the

retinoblastoma susceptibility gene, BBA Rev. Cancer, 43-61, 1155,
1993.

33

Liu H., Dibling B., Spike B., Dirlam A. and Macleod K., New roles for
the RB tumor suppressor protein, Curr. Opin. Genet. Dev., 5564,
14, 2004.

34

Sherr C.J., McCormick F., The RB and p53 pathways in cancer,

Cancer Cell , 103-112, 2, 2002.

35

Lipinski M.M., Jacks T., The retinoblastoma gene family in

differentiation and development, Oncogene, 7873-7882, 18, 1999.

36

Hahn W.C., Weinberg R.A., Modeling the molecular circuitry of

cancer, Nat. Rev. Cancer, 331-341, 2, 2002.

37

Hickman E.S., Moroni M.C., Helin K., The role of p53 and pRB in
apoptosis and cancer, Curr. Opin. Genet. Dev., 60-66, 12, 2002.

38

Chau B.N., Wang J.Y., Coordinated regulation of life and death by

RB, Nat. Rev. Cancer, 130-138, 3, 2003.

39

Sherr M.J., Roberts J.M., CDK inhibitors: Positive and negative

regulators of G1-phase progression, Genes Dev., 1501-1512, 13,
1999.

40

Schmitt C.A., Fridman J.S., Yang M., Lee S., Baranov E., Hoffman
R.M., Lowe S.W., A senescence program controlled by p53 and p16/
Ink4a contributes to the outcome of cancer therapy, Cell, 335-346,
109, 2002.

41

Lowe S.W., Sherr C.J., Tumor suppression by Ink4a-Arf: Progress

and puzzles, Curr. Opin. Genet. Dev., 77-83, 13, 2003.

42

Swanton C., Cell-cycle targeted therapies, Lancet Oncol., 27-36, 5,

2004.

43

Moroni M.C., Hickman E.S., Denchi E.L., Caprara G., Colli E., Cecconi
F., Muller H., Helin K., Apaf-1 is a transcriptional target for E2F and
p53, Nat. Cell Biol., 552-558, 3, 2001.

44

Nahle Z., Polakoff J., Davuluri R.V., McCurrach M.E., Jacobson M.D.,
Narita M., Zhang M.Q., Lazebnik Y., Bar-Sagi D., Lowe S.W., Direct
coupling of the cell cycle and cell death machinery by E2F, Nat. Cell
Biol., 859-864, 4, 2002.

45

Gage JR, Meyers C, Wettstein FO, The E7 proteins of the

nononcogenic human papillomavirus type 6b (HPV-6b) and of the
oncogenic HPV-16 differ in retinoblastoma protein binding and other
properties. J. Virol., 723-730, 64, 1990.

46

Hu Q.J., Dyson N., Harlow E., The regions of the retinoblastoma

protein needed for binding to adenovirus E1A or SV40 large T antigen
are common sites for mutations, EMBO J., 1147-1155, 9, 1990.

47

Horsthemke B., Genetics and cytogenetics of retinoblastoma,

Cancer Genet. Cytogenet., 1-7, 63,1992.

-125-

4:

48

Tsai T., Davalath S., Rankin C., Radich J.P., Head D., Appelbaum
F.R., Boldt D.H., Tumor suppressor gene alteration in adult acute
lymphoblastic leukemia (ALL). Analysis of retinoblastoma (Rb) and
p53 gene expression in lymphoblasts of patients with de novo,
relapsed, or refractory ALL treated in Southwest Oncology Group
studies, Leukemia, 1901-1910, 10, 1996.

49

Bartek J., Bartkova J., Lukas J., The retinoblastoma protein pathway
and the restriction point, Curr. Opin. Cell Biol., 805-814, 8, 1996.

50

Vogelstein B., Lane D. and Levine A.J., Surfing the p53 network,
Nature, 307-310, 408, 2000.

51

Hollstein M., Hergenhahn M., Yang Q., Bartsch H., Wang Z.-Q,
Hainaut P., New approaches to understanding p53 gene tumor
mutation spectra, Mutat. Res., 199209, 431, 1999.

52

Hussain S.P. and Harris C.C. p53 mutation spectrum and load: The
generation of hypotheses linking the exposure of endogenous or
exogenous carcinogens to human cancer, Mutat. Res., 2332, 428,
1999.

53

DeLeo A.B. , et al., Detection of a transformation-related antigen in

chemically induced sarcomas and other transformed cells of the
mouse, Proc. Natl. Acad. Sci. USA, 24202424, 76, 1979.

54

Lane D.P. and Crawford L.V., T antigen is bound to a host protein in

SV40-transformed cells, Nature , 261263, 278, 1979.

55

Lane D.P. and Lain S., Therapeutic exploitation of the p53 pathway,
Trends Mol. Med., S38-S42, 8, 2002.

56

Scheffner M. et al., The E6 oncoprotein encoded by human

papillomavirus types 16 and 18 promotes the degradation of p53,
Cell, 11291136, 63, 1990.

57

Greenblatt M.S. et al., Mutations in the p53 tumor suppressor gene:

Clues to cancer etiology and molecular pathogenesis, Cancer Res.,
48554878, 54, 1994

58

Hollstein M. et al., p53 mutations in human cancers, Science, 4953, 253, 1991.

59

Levine A.J. et al., The p53 tumour suppressor gene, Nature, 453456, 351, 1991.

60

Harris C.C., p53 tumor suppressor gene: From the basic research
laboratory to the clinic-An abridged historical perspective,
Carcinogenesis, 11871198, 17, 1996.

61

Oren M. and Rotter V., Introduction: p53the first twenty years,

Cell. Mol. Life Sci., 9-11, 55, 1999.

62

Zhou J. et al., A role for p53 in base excision repair, EMBO J., 914
923, 20, 2001.

63

Tyner S.D. et al., p53 mutant mice that display

ageingassociated phenotypes, Nature, 45-53, 415, 2002.

64

Hofseth L.J., Hussain S.P. and Harris C.C., p53: 25 years after its
discovery, Trends Pharmacol. Sci., 177-184, 24, 2004.

-126-

early

5: &

65

Vousden KH, Lu X., Live or let die: The cells response to p53, Nat.
Rev. Cancer, 594-604, 2, 2002.

66

Flores E.R., Tsai K.Y., Crowley D., Sengupta S., Yang A., McKeon F.,
Jacks T., p63 and p73 are required for p53-dependent apoptosis in
response to DNA damage, Nature, 560-564, 416, 2002.

67

Momand J., Wu H.H., Dasgupta G., MDM2-master regulator of the

p53 tumour suppressor protein, Gene, 15-29, 242, 2000.

68

Meek D.W., Mechanisms of switching on p53: A role for covalent

modification?, Oncogene , 76667675, 18, 1999.

69

Prives C. and Hall P.A., The p53 pathway, J. Pathol., 112-126, 187,
1999.

70

Giaccia A.J., Kastan M.B., The complexity of p53 modulation:

Emerging patterns from divergent signals, Genes Dev., 2973-2983,
12, 1998.

71

Carr A.M., Perspectives: Cell cycle: Piecing together the p53 puzzle,
Science, 17651766, 287, 2000.

72

Zheng H., You H., Zhou X.Z., Murray S.A., Uchida T., Wulf G., Gu L.,
Tang X., Lu K.P., Xiao Z.X., The prolyl isomerase Pin1 is a regulator
of p53 in genotoxic response, Nature, 849-853, 419, 2002.

73

Sherr C.J. and Weber J.D., The ARF/p53 pathway, Curr. Opin.
Genet. Dev., 94-99, 10, 2000.

74

Lowe S.W. and Lin A.W., Apoptosis in cancer, Carcinogenesis, 485495, 21, 2000.

75

Vousden H. and Van de Woude G.F., The ins and outs of p53, Nat.
Cell Biol., E178E180, 2, 2000.

76

Giannakakou P., Sackett D., Ward Y., Webster K.R., Blagosklonny

M.V., Fojo T., p53 is associated with microtubules and uses dyne
independent transport for nuclear accumulation, Nat. Cell Biol., 709717, 2, 2000.

77

Gostissa M., Hofmann T.G, Will H. and Del Sal G., Regulation of p53
functions: Lets meet at the nuclear bodies, Curr. Opin. Cell Biol.,
351-357, 15, 2003.

78

Levine A.J., p53, the cellular gatekeeper for growth and division,
Cell, 323331, 88, 1997.

79

Ohki R. et al., Reprimo, a new candidate mediator of the p53mediated cell cycle arrest at the G2 phase, J. Biol. Chem., 2262722630, 275, 2000.

80

Chan T.A. et al., 14-3-3 is required to prevent mitotic catastrophe

after DNA damage, Nature, 616620, 401, 1999.

81

Laronga C. et al., Association of the cyclin-dependent kinases and

14-3-3 sigma negatively regulates cell cycle progression, J. Biol.
Chem., 2310623112, 275, 2000.

82

El-Deiry W.S. Regulation of p53 downstream genes, Semin. Cancer

Biol., 345-357, 8, 1998.

-127-

4:

83

Reed J.C. Dysregulation of apoptosis in cancer, J. Clin. Oncol.,

29412953, 17, 1999.

84

Yin Y. et al., PAC1 phosphatase is a transcription target of p53 in

signalling apoptosis and growth suppression, Nature, 527-531, 422,
2003.

85

Haupt S. et al., Apoptosis-The p53 network, J. Cell Sci., 4077-4085,

116, 2003.

86

Tlsty T.D., Genomic instability and its role in neoplasia, Curr. Top.
Microbiol. Immunol., 3746, 221, 1997.

87

Wahl G.M. et al., Maintaining genetic stability through TP53

mediated checkpoint control, Cancer Surv., 183-219, 29, 1997.

88

Tanaka H. et al., A ribonucleotide reductase gene involved in a p53dependent cell-cycle checkpoint for DNA damage, Nature, 42-49,
404, 2000.

89

Nataraj A.J., Trent J.C., Ananthaswamy H.N., p53 gene mutations

and photocarcinogenesis, Photochem. Photobiol., 218-230, 62,
1995.

90

Crook T., Vousden K.H., Interaction of HPV E6 with p53 and

associated proteins, Biochem. Soc. Trans., 52-55, 22, 1994.

91

Lowe S.W., Bodis S., McClatchey A., Remington L., Ruley H.E., Fisher
D.E., Housman D.E., Jacks T., p53 status and the efficacy of cancer
therapy in vivo, Science, 807-810, 266, 1994.

92

Bueso-Ramos C.E., Manshouri T., Haidar M.A., Yang Y., McCown P.,
Ordonez N., Glassman A., Sneige N., Albitar M., Abnormal
expression of MDM-2 in breast carcinomas, Breast Cancer Res.
Treat., 179-188, 37, 1996.

93

Moller M.B., Ino Y., Gerdes A., Skjodt K., Louis D., Pedersen N.,
Aberration of the p53 pathway components p53, MDM2 and CDKN2A
appear independent in diffuse large B cell lymphoma, Leukemia,
453-459, 13, 1999.

94

Hussain S.P., and Harris C.C., Molecular epidemiology of human

cancer: contribution of mutation spectra studies of tumor suppressor
genes, Cancer Res., 40234037, 58, 1998.

95

Hussain S.P. et al., Increased p53 mutation load in nontumorous

human liver of Wilson disease and hemochromatosis: Oxyradical
overload diseases, Proc. Natl. Acad. Sci. USA, 12770-12775, 97,
2000.

96

Kirk G.D. et al., Ser-249 p53 mutations in plasma DNA of patients

with hepatocellular carcinoma from The Gambia, J. Natl. Cancer Inst.
, 148153, 92, 2001.

97

Appella E. and Anderson C.W., Post-translational modifications and

activation of p53 by genotoxic stresses, Eur. J. Biochem., 27642772, 268, 2001.

-128-

6:

,
,

,


.


,
,

.

,
.

CDKs. CDKs

,
,
1 .

CDKs.
CDKs (
).

-129-

6:

CDKs ( ). ,

, .

CDKs

CDKs

CDKs,
/ CDKs
CDKs, CDKs,
CDK7
cdc25 Wee1/Myt1
/ CDKs .

CDKs .
CDKs,
p16, p21, 27 p53, in vitro in vivo

2,3 . , , Lovastatin,
p21 27
G1 4 , rapamycin
p27
-2 5 .

CDKs .

CDKs

CDKs.

,
Drosophila,

p16

-130-

6:

pRb G1
6 .
, p21 CDK2
E2F1, -
Tat HIV ,
CDK2 S 7 .

CDKs /CDKs.
mRNAs CDKs
/ .
D1

8 . ,
D,
D1 D3 CDK2 CDK4
9,10 .
,

/CDKs

G1

pRb.

20S-

p27,
CDKs
11 .

-131-

6:

CDKs /
.

/

.
G2 stress
( -), G2
DNA.
,
12 . , G2

G2 .

CDKs
CDKs
.

.
,
.
CDK
13 , :
`

(<600)

, ,

ATP

CDK2 ,
- -
-83 (Leu83)
, -

-132-

6:

-81 (Glu81)
.
CDKs

,
,
.
ATP- CDK
14 .
,
CDKs /-
-

staurosporine
UCN-01.
CDK
, flavopiridol,

.

ATP CDKs
,
CDKs
. CDK2 CDKs
15 .
CDK2

,
cAMP- ,
PKA 16 . - ,
- ( , -lobe), -
- (- , C-lobe)

ATP. ,
, - (T-loop),
- , 1-
PSTAIRE,

-133-

6:

17 .

PSTAIRE, - - -
CDK2
18 . , -

,
.

Thr 160
/CDK2.

ATP,

ATP
.
CDKs
19 .

CDKs

p19/CDK6, CDK6,
,
. p19
-- (helix-loophelix). -
- - .
L 20 .
CDK2 ATP

,
Leu-83 N1, Glu-81 N(6)H2 Asp86 (2),
: Lys-33, Asn-132, Asp145, Lys-129, Thr-14 Wat-558 21 .

-134-

6:

ATP-

CDK 6dimethylaminopurine (6-DMAP).

,
, ,

22

1980

.
O 6-DMAP

1 23,24 ,
CDK1 (IC50=120 ) 25 .

in

vitro

p34cdc2/cyclinBcdc13
, isopentyladenine,
(IC50=55 )25, .

isopentyladenine ,

olomoucine 26 ,

CDK1 2 (IC50=7 ),
,
CDK4, 6 PKC,
2,6,9- . (R)roscovitine olomoucine,
,
10 (CDK2,IC50=0.7 ).
roscovitine

, purvalanols.
in vitro, IC50

0.004

0.005

27, 28 , 29 . purvalanol A
G1/S

G2/

CDK1 CDK2 .

-135-

6:

NCI purvalanol A (
IC502 )
purvalanol B,
, purvalanol B
.

R
HN

N
NH

HN

N
N

6-Dimethylaminopurine

NH

NH

OH

Cl
N

Purvalanol A (R=H)

Isopentyl adenine

Purvalanol B (R=CO2H)

NH
N

N
R

NH

Olomoucine: R= OH
Roscovitine:
Bohemine:

N
R1
R1= CH3

OH
OH

27.

isopentyladenine, olomoucine
roscovitine CDK2,
ATP
- ,
-ATP 30 . 160
ATP,
6--.

(backbone) Glu81

C8- olomoucine. 6 7 olomoucine

-136-

6:

3 Leu83 .

CDK ,

7-methyl-olomoucine

(iso-

26

olomoucine) . ATP Glu81

Leu83, roscovitine
Leu83 31 .
ATP
(1), (7)
roscovitine. purvalanol ,
olomoucine.

isopentyladenine

ATP olomoucine30.

ATP, 9 3
Glu81 -
Leu83, .
CDK2 olomoucine, 6cyclohexylmethylguanine (NU 2058)
NU6102.

purvalanols

, 2 PUR-1, CVT 313

PUR-2.

N
N

N
HO

Cl

N
OH

PUR-1

OCH3

OH
CVT 313

Cl
N

NH2

N
H

PUR-2

28.

-137-

6:

CDK 2,6,9-
.
,
G1 G2 ,
CDK1 CDK2 ,
Erk1/2 32,33 .
,

,
34 taxol 35 .
, .
,

roscovitine (CDK2 ) p16

(CDK6 ) 36 .
,

37

.

(R)-roscovitine in vitro in vivo .
, p.o.
38 ,

,
39 ,

40 .

flavopiridol (NSC
649890, L86-8275 HMR 1275) dechloroflavopiridol
rohitukine, o
Dysoxylum binectariferum 41, 42 , 43 . flavopiridol CDK
44 .
, genistein quercetin

.

-138-

6:

OH O

OH O

OH O

Cl
HO
HO

HO
HO

N
CH3

HO
HO

N
CH3

Flavopiridol

N
CH3

Dechloroflavopiridol

OH

OH O

CH3

Rohitukine

OH O
OH

HO

HO

Genistein

OH

OH

Quercetin

29.

flavopiridol
,
- EGFR (IC50=21-25 ) 45,46 ,

Src

IC50=50

) 47

, (PKA IC50=122-145
, PKC IC50=6 , Erk-1 IC50=16 )45,46,48 . , ,

60

NCI

IC50=66 n,
1000
PKC 49 .

G1/S

G2/

43

CDK1 2 .
flavopiridol ,
CDKs,
D/CDK4 (IC50=20-40 nM), D/CDK6 (IC50=60 nM)
B/CDK1 (IC50=30-40 nM),
A/CDK2, /CDK2 (IC50=100 nM) H/CDK7
(IC50=100-300

nM)45,47.

-139-

6:

3 (glycogen
synthase 3, GSK-3) IC50=450 nM 50 .
CDKs flavopiridol
D1,

. MCF-7
flavopiridol D1 3
,

D3,

D2 ,
CDK4,
D1 51 .
flavopiridol
52 : 1)
CDKs ATP, 2)
Thr160/161 CDKs
/CDK7 3)
D1 CDK4 6 (G1/S
).
flavopiridol

P-TEFb

(positive

53

transcription elongation factor b, P-TEFb) (IC50=6 nM) , -ATP ,

CDKs.

dechloroflavopiridol

CDK2

CDKs 54 .
ATP,
,
60 . CDK2
.
ATP
ATP.

dechloroflavopiridol CDK1 2,
. flavopiridol

-140-

6:

55 .

flavopiridol 56 .

. ,
.
.

chinol-4-one

. , (FLV-)1
(FLV-2)
/CDK1
/CDK2 D1/CDK455.

OH

HO

OH O

O
OH

HO

O
OH

Cl

N
CH3

O
Cl

N
CH3

FLV-1

FLV-2

30.

flavopiridol

CDKs.

42,

57

, Bcl-2/Bax
p53 58,59 .

60
VEGF ,
61 . ,

-141-

6:

CDKs
.

62

. flavopiridol

placitaxel, cytarabine, topotecan, doxorubicin,

etoposide 5-fluorouracil 63,64 .
flavopiridol



CDKs
in vitro 65, 66 , 67 .

, nonHodgkin , mantel cell

65,

68

flavopiridol,

, placitaxel, fludarabine, cytosine arabinoside

irinotecan67,69 ,
.
flavopiridol
CDK .

CDK2/ dechloroflavopiridol,

5--

4-

70

.
FLV-3.
CDK1 CDK 2 CDK4

GSK3.

-,

VEGFR2

EGFR

, .
HCT-116
( 1).

-142-

6:

OH

HO

SO2NH2

N
CH3
FLV-3

1. FLV-3
.

IC50 []

% 10

CDK1/B

CDK2/A

CDK4/D1

GSK3

PKC

KDR

EGFR

0.009

0.03

1.87

3.7

42

25

36

(butyrolactone)
o Aspergillus ( F25799)
CDKs .

OH
H3CO

HO

O
O

OH
O

Butyrolactone

ATP-

CDK1 CDK2 (IC50=0.82

M), , MAPK,
PKC, EFGR 71 . , ,

-143-

6:

pRb
0.48-31M 171.
S G1/M,
CDK1 2 72 .

,

IC50 50
g/mL 73 .
74 .

[2,3-a]

staurosporine ,

indolo[2,3-a]carbazole
Streptomyces

staurosporeus

ATP-

.
PKC (IC50=2 nM) 75 .
CDKs ( /CDK1
IC50=3.2 nM, /CDK2 IC50=7 nM, D/CDK4 IC50=3-10
M) 76, 77 , 78 .

.

staurosporine

ATP
.

ATP,
-

staurosporine CDK2
83%

)
-.
1000
staurosporine CSK
- Asp86

-144-

6:

Gln131
.
CK1, CK2 MAPK.

H
N

H
N

HO

H3C

N
N

H
N

H3C

N
H3C

NHCH3

NHCH3

R
N

N-benzoxystaurosporine
H
N

O
H2 N

NH2

N O N
H

N O N
CH3

HO

H3C

UCN-01
(7-hydroxystaurosporine)

Staurosporine

H3CO

H3CO

H3CO

CH2OH

CH3
HO

KT6124: R = NH2
KT6528: R = OH

COOCH3

K-252a

31. [2,3-a].

staurosporine

PKC
. , UCN-01 (7hydroxystaurosporine)
PKC (IC50=6.8 nM), CDK1 (IC50=31 nM), CDK2 (IC50=30 nM),
Raf-1 (IC50=620 nM) MAPK
(IC50=910 nM). UCN-01

A549

pRb
G1/S 79 .
UCN-01
G1 G2 (IC50~50 nM)
CDKs ( CDK1)65,80 ,

-145-

6:

cdc25c Chk1 81 . UCN-01

G1 G2
,
cisplatin gemcitabine 82 .
UCN-01

Akt,

83

.
UCN-01,


1 84 . ,
, , ,
.
.
, K-252a, KT6124
KT6528 PKC ,

85,86 .
, CGP41251 (N-benzoxystaurosporine)
PKC (IC50=50 nM) 87 .

NU2058,

ATP-

CDK1 (IC50=5 M) CDK2 (IC50=12 M),

CDK4 88 .
NU2058 CDK2
P 6-
, roscovitine purvalanol.
-9
Glu81, N3 Leu83 2-2 Leu8388.
-

, 9 89 .

-146-

6:

CDK ,

NU6027,

CDK1 (IC50=2.5 M) CDK2

(IC50=1.3 M)88. NU6027 CDK2
, 5-
,
6-2

Glu81. NU6027

roscovitine ,
.

90

PYR-1 CDK4 (IC50=1.5 M) .

CDK6 (IC50=5.6 M) CDK5 (IC50=25 M),
50 M
CDK1 2. , pRb
G1
pRb(+),
p16

O
N

N
HN

N
H

HO

O
H
O
N

N
H
SO2NH2
PYR-1

N
H

N
H

O
H

NU6027

N
N
H

N
H

PYR-1

32. .

6-
NU2058 CDK2
- 2

-147-

6:

ATP. , NU6102
1000 (CDK1, IC50=9 nM
CDK2, IC50=6 nM) NU2058.

NU6102/CDK2
Asp86 91 .

92

6
5
NU6027,

PYR-2,

500 CDK1 1000

CDK2 (IC50=0.0011 nM),

.
[2,3-d]
, 6--,
PPO-1,
-

(EGFR,

FGFR,

PDGFR)

93

(c-Src) .
Cl

N
H

N
H

N
O
CH3

Cl
PPO-2
N

N
N

PPO-1
N

N
N
CH3
PPO-3

OH
PPO-4

6- CDK .

-148-

6:

, PPO-2 CDKs

(c-Src, EGFR)

D/CDK4 (IC50=0.62 M) 94 . PPO3

, PPO-4
CDK4.

2. [2,3-d] .

CDK1/B

CDK2/A

CDK2/E

CDK4/D

FGFR

PPO-2

1.015

0.129

0.41

0.620

3.295

PPO-3

0.079

0.015

0.020

0.004

0.051

PPO-4

>40

0.209

0.165

0.008

8.62

K deaza pyrido[2,3-d]pyrimidones
RTKs 95 .
96 .
D-QUIN-1,
EFGR, IC50 29
pM 97 , CDK2 (IC50=250
M)96.

NH
NH

Br

OCH3

OCH3

N
D-QUIN-1

33.

Cl3C

OCH3

NH2

F3C
OCH3

N
D-QUIN-2

D-QUIN-3

deaza

CDK

, D-QUIN-2
CDK2/ (IC50=13.5 M) CDK1/ (IC50=15 M),

-149-

6:

98 : (CF3,
CCl3) 2,
(tBu, tamyl) 4. ,
6.
D-QUIN-3
/CDK2 (IC50=2.1 M).

4000

,
.
5500 ,
100.000-500.000 99,100 .

101 .

.
Danggui Longhui Wan, 11

102 .
indirubin 1966.
indirubin
CDKs . ,
DNA 103 in vivo
Walker-256 104 .
,
. , indirubin
sulfate indirubin monoxime,
CDK1, 2 5 CDK4.
indirubin sulfate CDK2
ATP-

:

-150-

6:

Glu81, Leu83

Leu83 105 .
indirubin sulfate CDK

,
. indirubin monoxime,

,
G1
G2/ , CDK1 CDK2 106 .
GSK3 IND-1
107 .

HO3S
O

N
H

I
HO

O
NH

Indirubin

NH

N
H

Indirubin sulfate

N
H

HO

NH

N
H

Indirubin monoxime

N
H
O

H
N
R1

N
H

IND-2

OH

H
N
O

NH
O

IND-1

O
N

O
O

N
H

R2

UR-1, R1 = H, R2 = H
UR-2, R1 = Cl, R2 = CF3

IND-3

34. o .

IND-2, IND-3
UR-1 UR-2,
D1/CDK4, IND-2
MCF-7 ZR-75-1,
pRb(-) BT-549
(IC50=13.9 M) 108 .

-151-

6:

3,5-
SU9516 , -,
CDK2 (IC50=0.022 M), CDK1 (IC50=0.04 M) CDK4
(IC50=0.2 M), PKC, p38,
PDGFR

EGFR

(IC50>10 M)

109

. SU5416,

-,
VEGFR-1 110 . MAZ51
VEGFR-3
111 .
H SU9516 CDK2
3 CDK2 112 :
NHCO

N
H
O

H3CO

N
H
O

N
H

N
H

SU-9516

N
H

SU-5416
O2S N
H

SO2NH2

MAZ-51
O2S N
H

OH
B
r

N NH

S
N

INDET-1

NH

O
N
H

NH
O

N
H

N
H

INDET-2

INDET-3

35. o .

4-, 5-, 3- 4-
CDK2.

5- ,

-152-

6:

His84 Gln85. , 6- 7-
Phe80.
5-
CDK2, 5- - (SU5416 113 , SU6668 114 )
- 115 VEGFR-2,
FGFR-1, PDGFR- . 5-

5--,

CDK2

116

.
INDET-1
CDK2 (IC50=60 nM)
. 4,5
INDET-2 CDK2 (IC50=0.54 nM),
INDET-3 CDK2
(IC50=9.7nM), CDK1 (IC50=100 nM) CDK4 (IC50=130 nM)
GSK-3 (IC50=56 nM) VEGFR-2
(IC50=22 nM).

Paullones
paullones
Compare NCI CDK
. (seed) flavopiridol,

kenpaullone
60 NCI
flavopiridol. kenpaullone ATP
CDK1, 2 5,
c-Src (IC50=15 M), 2 (IC50=20 M), Erk1
(IC50=20 M) Erk2 (IC50=9 M) 117 . ,

flavopiridol

,
kenpaullone

-153-

6:

alsterpaullone PAUL-1,
CDK1.

H
N

O
7

HN

12

Kenpaullone, R = Br
Alsterpaullone, R=NO2
PAUL-1,
R=CN

3. (M)
paullones.
CDK1
/B

CDK2
/A

CDK2
/E

CDK4
/D

CDK5
/p25

GSK-3

0.4

0.68

7.5

>100

0.85

0.023

Alsterpaullone

0.035

0.015

0.2

>10

0.04

0.004

PAUL-1

0.024

0.044

0.01

Kenpaullone

118 :
9 CDK .
9-Br 2-, 10- 11-,
(CH3, OCH3)
CDK1 .
9-Br 9-CN 9-NO2 CDK1
. 2-Br
(paullone) 2-, 3- OCH3
CDK1 . , 4
,

4- OCH3-kenpaullone

CDK1 .
/
, ( Boc-)
CDK1. ,
S-lactam, thioimidate, hydroxyamidine
.
in vitro paullones

-154-

6:

CDK.

, alsterpaullone
kenpaullone 100 ., PAUL-1,
CDK1
alsterpaullone, in vitro
. , Boc ,
methylthioimidate NHCO
,
CDK1 .
2
-, -

CDK1 in vitro
119 .

paullones ATP
CDKs. CDKs, paullones
GSK3- GSK3- 120 .
alsterpaullone
GSK3- (IC50=0.004 M).

ATP.
paullone, gwenpaullone,

,
CDKs GSK3,
paullones,

(malate dehydrogenase, MDH), alsterpaullone
IC50=6.20 M 121 .

paullones Leishmania mexicana,
.
paullones ,
alsterpaullone

(clonogenicity)

Jurkat 122 . , alsterpaullone

-155-

6:

8 9,
-3 poly(ADP-ribose) polymerase. ,

, XIAP Bcl-xl.

GSK-3

CDKs

kenpaullone 123 .

(PAULET-1, 2, 3) kenpaullone ,
.
1-azakenpaullone GSK3 (IC50=0.018 M) GSK-3
CDK1.

H
N

H
N

H
N

N
HN

HN

HN
Br

Br
PAULET-1

PAULET-2

Br
PAULET-3

36. paullones.

Fascaplysin

N
N
O
Facaplysin

fascaplysin 1998
Fascaplysinopsis Bergquist sp.

124

-156-

6:

Staphylococcus

aureus,

Escherichia coli, Candida albicans Saccharomyces cerevisiae

L-1210
(ED50=0.2 g/mL)124,
Ehrlich,
, 50 g/mL.
fascaplysin
CDK4/D1 (IC50=0.35 M) CDK6/D1 (IC50=3.4 M) 125 .

. ,

100

50%

CDK4/D2, D3
v-abl, c-met, IGF-1R o insulin-R,
10M.

CDKs (U2OS, HCT-116) (MRC-5),

G1 . , CDKs,
fascaplysin

126 .
, . ,
, CDK4,6
.

Hymenialdsisine
H

hymenialdsisine

[2,3-c]

(glycocyamidine)
(aldisines). (Hymeniacidon
aldis, Axinell verrucossa Acantella aurantiaca)
1980

127, 128 , 129 , 130 , 131 .

CDKs, CDK1/ (IC50=22 nM), CDK2/A (IC50=70 nM),

-157-

6:

CDK2/E (IC50=40 nM), CDK5/p25 (IC50=28 nM),

GSK-3 (IC50=10 nM ) CK1 (IC50=35 nM ) 132 .
, hymenialdsisine
Stylissa massa

Raf/Mek-1/MAPK,

Mek-1 (IC50= 6 nM )
MAPK 133 .
, Ras
30% .
hymenialdsisine
ATP- 132,
CDK2

CDKs/.
,
ATP, indirubin,
. ,

Asp145, .
Van der Waals -
ATP
.

hymenialdsisine

. ,
hymenialdsisine
M ,
CDKs Mek-1133.

U937, hymenialdsisine NFB. , ,

Alzheimers,
132

in vitro hymenialdsisine (IC50=50 M )

-158-

6:

H2N

N
O

HN
Br
N
H

NH
O

Hymenialdisine
H
R N
X

H2N

NH
O

X
N
H

NH
O

R2

R1

N
H

N
NH
N

HN

NH

N
H

NH
O

NHR

N
H

NH
O

37. Hymenialdisine .

133 hymenialdsisine
60
. 11
,
, p90RSK, KDR, c-Kit, Fes, MAPK1, PAK2, PDK1, PKC,
PKD2, Rsk1 SGK,
nM .
CDKs GSK-3
,
30 134 .

CDK4,
Compare

p16 135 .

, AC-1 BNZ-1
CDK4 . ,

CDK ,
DNA 136 .
AC-1

(NCS625987) BNZ-1

(NCS545787)

-159-

6:

N
H

NH2

O
N
N

HN

AC-1

BNZ-1

38. .

CDK4 CDK6
, CDK4
CDK4 CDK2 (72%

ATP) 137,138 .

CDK

-.
52 CDK4 (IC50= 42 nM),
PKA, PKC, MEK1, Src EFGR.
53 CDK4
(IC50= 29 nM).
CDK4
ATP
CDK2.
CDK4/CDK2,

CDK2

52 139 .

ATP
52
CDK4. 54 CDK4 (IC50= 2
nM),
Molt-4, pRb(+) G1
0.1 0.5 .

-160-

N
O

N
H
N

N
NH

6:

HN
N
H
N

O
DLD-1

NH
O

DLD-2

N
O

HN
N
H
N

NH

NH
O

Cl

DLD-3

39. .

Senderowicz A.M., Sausville E.A., Preclinical and clinical

development of cyclin-dependent kinase modulators, J. Nat. Can.
Inst., 376-387, 92, 2000.

Chintala SK, Fueyo J, Gomez-Manzano C, Venkaiah B, Bjerkvig R,

Yung WK, et al., Adenovirus-mediated p16/CDKN2 gene transfer
suppresses glioma invasion in vitro, Oncogene, 20492057, 15,
1997.

Eastham JA, Hall SJ, Sehgal I, Wang J, Timme TL, Yang G, et al., In
vivo gene therapy with p53 or p21 adenovirus for prostate cancer,
Cancer Res., 51515155, 55, 1995.

Lee S.J., Ha M.J., Lee J., Nguyen P., Choi Y.H., Pirnia F., et al.
Inhibition of the 3-hydroxy-3-methylglutaryl-coenzyme A reductase
pathway induces p53-independent transcriptional regulation of
p21(WAF1/CIP1) in human prostate carcinoma cells, J. Biol. Chem.
1061810623, 273, 1998.

Hashemolhosseini S., Nagamine Y., Morley S.J., Desrivieres S.,

Mercep L., Ferrari S., Rapamycin inhibition of the G1 to S transition
is mediated by effects on cyclin D1 mRNA and protein stability, J.
Biol. Chem., 1442414429, 273, 1998.

Fahraeus R., Paramio J.M., Ball K.L., Lain S., Lane D.P. Inhibition of
pRb phosphorylation and cell-cycle progression by a 20-residue
peptide derived from p16CDKN2/INK4A, Curr. Biol., 8491, 6, 1996.

Chen Y.N., Sharma S.K., Ramsey T.M., Jiang L., Martin M.S., Baker
K., et al., Selective killing of transformed cells by cyclin/cyclindependent kinase 2 antagonists, Proc. Natl. Acad. Sci. USA, 4325
4329, 96, 1999.

Kornmann M., Arber N., Korc M., Inhibition of basal and

mitogenstimulated pancreatic cancer cell growth by cyclin D1
antisense is associated with loss of tumorigenicity and potentiation of
cytotoxicity to cisplatinum, J. Clin. Invest., 344352, 101, 1998.

-161-

6:

Watts C.K., Sweeney K.J., Warlters A., Musgrove E.A., Sutherland

R.L., Antiestrogen regulation of cell cycle progression and cyclin D1
gene expression in MCF-7 human breast cancer cells, Breast Cancer
Res. Tr., 95105, 31, 1994.

10

Zhou Q., Stetler-Stevenson M., Steeg P.S., Inhibition of cyclin D

expression in human breast carcinoma cells by retinoids in vitro,
Oncogene, 107115, 15, 1997

11

Adams J., Palombella V.J., Sausville E.A., Johnson J., Destree A.,
Lazarus D.D., et al., Proteasome inhibitors: A novel class of potent
and effective antitumor agents, Cancer Res., 26152622, 59, 1999.

12

Roberge M., Berlinck R.G., Xu L., Anderson H.J., Lim L.Y., Curman D.,
et al., High-throughput assay for G2 checkpoint inhibitors and
identification of the structurally novel compound isogranulatimide,
Cancer Res., 57015706, 58, 1998.

13

Knockaert M., Greengard P. and Meijer L., Pharmacological inhibitors

of cyclin-dependent kinases, Trends Pharmacol. Sci., 417-425, 23,
2002.

14

Huwe A., Mazitschek R., and Giannis A, Small molecules as inhibitors

of cyclin-dependent kinases, Angew. Chem. Int. Ed., 21222138,
42, 2003.

15

De Bondt H.L., Rosenblatt J., Jancarik J., Jones H.D., Morgan D.O.
and Kim S.H., Crystal structure of cyclin-dependent kinase 2,
Nature, 595-602, 363, 1993.

16

Knighton D.R., Zheng J.H., Ten Kyck L.F., Ashford V.A., Xuong N.H.,
Taylor S.S. and Sowadski J.M., Crystal structure of the catalytic
subunit of cyclic adenosine monophosphate-dependent protein
kinase, Science, 407-414, 253, 1991.

17

Pavletich N.P., Mechanisms of cyclin-dependent kinase regulation:

Structures of Cdks, their cyclin activators, and Cip and INK4
inhibitors, J. Mol. Biol., 821-828 , 287, 1999.

18

Jeffrey P.D., Russo A.A., Polyak K., Gibbs E., Hurwitz J., Massague J.,
Pavletich N.P., Mechanism of CDK activation revealed by the
structure of a cyclinA-CDK2 complex, Nature, 313-320, 376, 1995.

19

Gray N., Detivaud L., Doerig C., Meijer L., ATP-site directed
inhibitors of cyclin-dependent kinases, Curr. Med. Chem., 859-875,
9, 1999.

20

Brotherton D.H., Dhanaraj V., Wick S., Brizuela L., Domaille P.J.,
Volyanik E., Xu X., Parisini E., Smith B.O., Archer S.J., Serrano M.,
Brenner S.L., Blundell T.L., Laue E.D., Crystal structure of the
complex of the cyclin d-dependent kinase CDK6 bound to the cell
cycle inhibitor p19ink4d, Nature, 244-250, 395, 1998.

21

Kim S.-H., Structure-based inhibitor design for CDK2, a cell cycle

controlling protein kinase, Pure Appl. Chem., 555-565, 70, 1998.

22

Rebhun L.I., White D., Sander G., Ivy N., Cleavage inhibition in
marine eggs by puromycin and 6-dimethylaminopurine, Exp. Cell
Res., 312-318, 77, 1973.

-162-

6:

23

Meijer L., Pondaven P., Cyclic activation of histone H1 kinase during

the sea urchin egg mitotic divisions, Exp. Cell Res., 116-129, 174,
1988.

24

Neant I., Guerrier P., 6-Dimethylaminopurine blocks starfish oocyte

maturation by inhibiting a relevant protein kinase activity, Exp. Cell
Res., 68-79, 176, 1988.

25

Rialet V., Meijer L., A new screening test for antimitotic compounds
using the universal M phase-specific protein kinase, p34cdc2/cyclin
Bcdc13, affinity-immobilized on p13suc1-coated microtitration
plates, Anticancer Res., 1581-1590, 11, 1991.

26

Vesely J., Havlicek L., Strnad M., Blow J.J., Donella-Deana A., Pinna,
L., Letham D.S., Kato J.Y., Detivaud L.,
Leclerc S., Meijer L.,
Inhibition of cyclin-dependent kinases by purine derivatives, Eur. J
Biochem., 771-786, 224, 1994.

27

Gray N., Wodicka L., Thunnissen A.M., Norman T., Kwon S., Espinoza
F.H., Morgan D.O., Barnes G., Leclerc S., Meijer L., Kim S.H.,
Lockhart D.J., Schultz P., Exploiting chemical libraries, structure, and
genomics in the search for new kinase inhibitors, Science, 533-538,
281, 1998.

28

Rosania G.R., Merlie J.Jr., Gray N., Chang Y.T., Schultz P.G., Heald
R., A cyclin-dependent kinase inhibitor inducing cancer cell
differentiation: Biochemical identification using Xenopus egg
extracts, Proc. Natl. Acad. Sci. USA, 4797-4802, 96, 1999.

29

Chang Y.T., Gray N.G., Rosania G.R., Sutherlin D.P., Kwon S.,
Norman T.C., Sarohia R., Leost M., Meijer L., Schultz P.G., Synthesis
and application of functionally diverse 2,6,9-trisubstituted purine
libraries as CDK inhibitors, Chem. Biol., 361- 375, 6, 1999.

30

Schulze-Gahmen U., Brandsen J., Jones H.D., Morgan D.O., Meijer

L., Vesely J., Kim S.H., Multiple modes of ligand recognition: Crystal
structures of cyclin-dependent protein kinase 2 in complex with ATP
and two inhibitors, olomoucine and isopentenyladenine, Proteins
Struct. Funct. Genet., 378391, 22, 1995.

31

De Azevedo W.F., Leclerc S., Meijer L., Havlicek L., Strnad M., Kim
S.H., Inhibition of cyclin-dependent kinases by purine analogs.
Crystal structure of human cdk2 complexed with roscovitine, Eur. J.
Biochem., 518526, 243, 1997.

32

Knockaert M., Lenormand P., Gray N., Schultz P., Pouyssegur J.,
Meijer L., p42/p44MAPKS are intracellular targets of the CDK
inhibitor purvalanol, Oncogene, 6413-6424, 21, 2002.

33

Villerbu N., Gaben A.M., Redeuilh G., Mester J., Cellular effects of
purvalanol A: A specific inhibitor of cyclin-dependent kinase
activities, Int. J. Cancer, 761-769, 97, 2002.

34

Edamatsu H., Gau C.L., Nemoto T., Guo L., Tamanoi F., Cdk
inhibitors,
roscovitine
and
olomoucine,
synergize
with
farnesyltransferase inhibitor (FTI) to induce efficient apoptosis of
human cancer cell lines, Oncogene, 3059-3068, 19, 2000.

35

OConnor D.S., Wall N.R., Porter A.C., Altieri D.C., A p34-(cdc2)

survival checkpoint in cancer, Cancer Cell, 43-54, 2, 2002.

-163-

6:

36

Matushansky I., Radparvar F., Skoultchi A.I., Reprogramming

leukemic cells to terminal differentiation by inhibiting specific cyclindependent kinases in G1, Proc. Natl. Acad. Sci. USA, 14317-14322,
97, 2000.

37

Borgne A., Golsteyn R.M., The role of cyclin-dependent kinases in

apoptosis, Prog. Cell Cycle Res., 453-459, 5, 2003

38

McClue S.J., Blake D., Clarke R., Cowan A., Cummings L.,et al, In
vitro and in vivo antitumor properties of the cyclin dependent kinase
inhibitor CYC202 (R-roscovitine), Int. J. Cancer, 463-468, 102, 2002.

39

Meijer L., Raymond E., Roscovitine and other purines as kinase

inhibitors. From starfish oocytes to clinical trials, Acc. Chem. Res.,
417-425, 36, 2003.

40

Senderowitz A.M., Novel small molecule cyclin-dependent kinases

modulators in human clinical trials, Cancer Biol. Ther., S84-S95, 4
(suppl.1), 2003.

41

Harmon A.D., Weiss U., Silverton J.V., The structure of rohitukine,

the main alkaloid of Amoora rohituka (Syn. Aphanamixis polystachya)
(meliaceae), Tet. Lett., 721724, 20, 1979.

42

Arguello F., Alexander M., Sterry J.A., Tudor G., Smith E.M., Kalavar
N.T., Greene J.F.Jr., Koss W., Morgan C.D., Stinson S., Siford T.J.,
Alvord W.G., Klabansky R.L., Sausville E.A., Flavopiridol induces
apoptosis of normal lymphoid cells, causes immunosuppression, and
has potent antitumor activity in vivo against human leukemia and
lymphoma xenografts, Blood, 24822490 ,91, 1998.

43

Kaur G., Stetler-Stevenson M., Sebers S., Worland P., Sedlacek H.,
Myers C., Czech J., Naik R., Sausville E., Growth inhibition with
reversible cell cycle arrest of carcinoma cells by flavone L 868275, J.
Natl. Cancer Inst., 17361740, 84, 1992.

44

Senderowicz A.M., Flavopiridol: The first cyclin-dependent kinase

inhibitor in human clinical trials, Invest. New Drugs, 313320, 17,
1999.

45

Losiewicz M.D., Carlson B.A., Kaur G., Sausville E.A., Worland P.J.,
Potent inhibition of CDC2 kinase activity by the flavonoid L86-8275,
Biochem. Biophys. Res. Commun., 589595, 201, 1994.

46

Sedlacek H.H., Hoffmann D., Czech J., Kolar C., Seemann G.,
Guessow D., Bosslet K., The change in research for the therapy of
tumors, Chimia, 311316, 45, 1991.

47

Sedlacek H.H., Mechanisms of action of flavopiridol, Crit. Rev.

Oncol. Hematol., 139170, 38, 2001.

48

Czech J., Hoffmann D., Naik R., Sedlacek H.-H., Antitumoral activity
of flavone L86-8275, Int. J. Oncol., 3136, 6, 1995.

49

Sedlacek H.H., Czech J., Naik R., Kaur G., Worland P., Losiewicz M.,
Parker B., Carlson B., Smith A., Senderowicz A., Sausville E.,
Flavopiridol (L86-8275, NSC-649890), a new kinase inhibitor for
tumor therapy, Int. J. Oncol., 1143-1168, 9, 1996.

50

Leclerc S., Garnier M., Hoessel R., Marko D., Bibb J.A., Snyder G.L.,
Greengard P., Biernat J., Wu Y.Z., E. Mandelkow M., Eisenbrand G.,

-164-

6:

Meijer L., Indirubins inhibit glycogen synthase kinase-3 and

CDK5/p25, two protein kinases involved in abnormal tau
phosphorylation in Alzheimer's disease. A property common to most
cyclin-dependent kinase inhibitors?, J. Biol. Chem., 251260, 276,
2001.
51

Carlson B., Lahusen T., Singh S., Loaiza-Perez A., Worland P.J.,
Pestell R., Albanese C., Sausville E.A., Senderowicz A.M.,
Downregulation of cyclin D1 by transcriptional repression in MCF-7
human breast carcinoma cells induced by flavopiridol, Cancer Res.,
4634, 59, 1999.

52

Senderowicz A.M., Novel direct and indirect cyclin-dependent kinase

modulators for the prevention and treatment of human neoplasms,
Cancer Chemother. Pharmacol., S61S73, 52(Suppl 1), 2003.

53

Chao S.H., Fujinaga K., Marion J.E., Taube R., Sausville E.A.,
Senderowicz A.M., Peterlin B.M., Price D.H., Flavopiridol inhibits PTEFb and blocks HIV-1 replication, J. Biol. Chem., 2834528348,
275, 2000.

54

De Azevedo W.F. Jr., Mueller-Dieckmann H.J., Schulze-Gahmen U.,

Worland P.J., Sausville E., Kim S.H., Structural basis for specificity
and potency of a flavonoid inhibitor of human CDK2, a cell cycle
kinase, Proc. Natl. Acad. Sci. USA, 27352740, 93, 1996.

55

Kim K.S., Sack J.S., Tokarski J.S., Qian L., S. Chao T., Leith L., Kelly
Y.F., Misra R.N., Hunt J.T., Kimball S.D., Humphreys W.G., Wautlet
B.S., Mulheron J.G., Webster K.R., Thio- and oxoflavopiridols, cyclindependent kinase 1-selective inhibitors: Synthesis and biological
effects, J. Med. Chem., 41264134, 43, 2000.

56

Murthi K.K., Dubay M., McClure C., Brizuela L., Boisclair M.D.,
Worland P.J., Mansuri M.M., Pal K., Structure-activity relationship
studies of flavopiridol analogues, Bioorg. Med. Chem. Lett., 1037
1041, 10, 2000.

57

Byrd J.C., Shinn C., Waselenko J.K., Fuchs E.J., Lehman T.A., Nguyen
P.L., Flinn I.W., Diehl L.F., Sausville E., Grever M.R., Flavopiridol
induces apoptosis in chronic lymphocytic leukemia cells via activation
of caspase-3 without evidence of bcl-2 modulation or dependence on
functional p53, Blood, 3804-3816, 92, 1998.

58

Parker B., Kaur G., Nieves-Neira W., Taimi M., Kolhagen G., Shimizu
T., Pommier Y., Sausville E., Senderowicz A.M., Early induction of
apoptosis in hematopoietic cell lines after exposure to flavopiridol,
Blood, 458-465, 91, 1998.

59

Shapiro G.I., Koestner D.A., Matranga C.B., Rollins B.J., Flavopiridol

induces cell cycle arrest and p53-independent apoptosis in non-small
cell lung cancer cell lines, Clin Cancer Res., 2925-2938, 5, 1999.

60

Brusselbach S., Nettelbeck D.M., Sedlacek H.H., Muller R., Cell

cycle-independent induction of apoptosis by the antitumor drug
flavopiridol in endothelial cells, Int. J. Cancer, 146-152, 77, 1998.

61

Melillo G., Sausville E.A., Cloud K., Lahusen T., Varesio L.,
Senderowicz A.M., Flavopiridol, a protein kinase inhibitor, downregulates hypoxic induction of vascular endothelial growth factor

-165-

6:

expression in human monocytes, Cancer Res., 5433-5437, 59,

1999.
62

Lee H.R., Chang T.H., Tebalt M.J., Senderowicz A.M., Szabo E.,
"Induction of differentiation accompanies inhibition of CDK2 in a nonsmall cell lung cancer cell line, Int. J. Oncol., 161-166, 15, 1999.

63

Bible K.C., Kaufmann S.H., Cytotoxic synergy between flavopiridol

(NSC 649890, L86-8275) and various antineoplastic agents: The
importance of sequence of administration, Cancer Res., 3375-3380,
57, 1997.

64

Schwartz G., Farsi K., Maslak P., Kelsen D., Spriggs D., Potentiation
of apoptosis by flavopiridol in mitomycin-C treated gastric and breast
cancer cells, Clin. Cancer Res., 1467-1472, 3, 1997.

65

Senderowicz A.M., The cell cycle as a target for cancer therapy:

Basic and clinical findings with the small molecule inhibitors
flavopiridol and UCN-01, Oncologist, 12-19, 7, 2002.

66

Zhai S., Senderowicz A.M., Sausville E.A., Figg W.D., Flavopiridol, a

novel cyclin-dependent kinase inhibitor, in clinical development, Ann.
Pharmacol., 905-911, 36, 2002.

67

Colevas D., Blaylock B., Gravell A., Current clinical trials of

flavopiridol, Oncology, 1204-1214., 16, 2002.

68

Sausville E.A., Elsayed Y., Monga M., Kim G., Signal transduction
directed cancer treatments, Annu. Rev. Pharmacol. Toxicol., 199231, 43, 2003.

69

Schwartz G.K., OReilly E., Ilson D., Saltz L., Sharma S., Tong W.,
Maslak P., Stoltz M., Eden L., Perkins P et al., Phase I study of
cyclin-dependent kinase inhibitor flavopiridol in combination with
paclitaxel in patients with advanced solid tumors, J. Clin. Oncol.,
2157-2170, 20, 2002.

70

Schoepfer J., Fretz H., Chaudhuri B., Muller L., Seeber E., Meijer L.,
Lozach O., Vangrevelinghe E., Furet P., Structure-based design and
synthesis
of
2-benzylidene-benzofuran-3-ones
as
flavopiridol
mimics, J. Med. Chem., 17411747, 45, 2002.

71

Kitagawa M., Okabe T., Ogino H., Matsumoto H., Suzuki-Takahashi I.,
Kokubo T., Higashi H., Saitoh S., Taya Y., Yasuda H., Butyrolactone
I, a selective inhibitor of cdk2 and cdc2 kinase, Oncogene, 2425
2432, 8, 1993.

72

Kitagawa M., Higashi H., Takahashi I.S., Okabe T., Ogino H., Taya Y.,
Hishimura S., Okuyama A., A cyclin-dependent kinase inhibitor,
butyrolactone I, inhibits phosphorylation of RB protein and cell cycle
progression, Oncogene, 25492557, 9, 1994.

73

Wada M., Hosotani R., Lee J.U., Doi R., Koshiba T., Fujimoto K.,
Miyamoto Y., Tsuji S., Nakajima S., Okuyama A., Imamura M., An
exogenous cdk inhibitor, butyrolactone-I, induces apoptosis with
increased Bax/Bcl-2 ratio in p53-mutated pancreatic cancer cells,
Anticancer Res., 2559-2566, 18, 1998.

74

Nishio K., Ishida T., Arioka H., Kurokawa H., Fukuoka K., Nomoto T.,
Fukumoto H., Yokote H., Saijo N., Antitumor effects of butyrolactone

-166-

6:

I, a selective cdc2 kinase inhibitor, on human lung cancer cell lines,

Anticancer Res., 3387-3395, 16, 1996.
75

Omura S., Iwai Y., Hirano A., Nakagawa A., Awaya J., Tsuchya H.,
Takahashi Y., Masuma R., A new alkaloid AM-2282 of streptomyces
origin.
Taxonomy,
fermentation,
isolation
and
preliminary
characterization, J. Antibiot., 275282, 30, 1977.

76

Meijer L., Chemical inhibitors of cyclin-dependent kinases, Trends

Cell. Biol., 393-397, 6, 1996.

77

Gadbois D., Hamaguchi J.R., Swank R.A., Bradbury E.M.,

Staurosporine is a potent inhibitor of p34cdc2 and p34cdc2-like
kinases., Biochem. Biophys. Res. Commun., 80-85, 184, 1992.

78

Meijer L., Chemical inhibitors of cyclin-dependent kinases, Prog.

Cell Cycle Res., 351-361, 1, 1995.

79

Seynaeve C.M., Stetler S.M., Sebers S., Kaur G., Sausville E.A.,
Worland P.J., Cell cycle arrest and growth inhibition by the protein
kinase antagonist ucn-01 in human breast carcinoma, Cancer Res.,
2081-2086, 53, 1993.

80

Dai Y., Yu C., Singh V., Tang L., Wang Z., McInistry R., Dent P.,
Grant S., Pharmacological inhibitors of the mitogen-activated protein
kinase (MAPK) kinase/MAPK cascade interact synergistically with
UCN-01 to induce mitochondrial dysfunction and apoptosis in human
leukemia cells, Cancer Res., 5106-5115, 61, 2001.

81

Graves P.R., Yu L., Schwarz J.K., Gales J., Sausville E.A., OConnor
P.M., Piwnica-Worms H., The Chk1 protein kinase and the Cdc25C
regulatory pathways are targets of the anticancer agent UCN-01, J.
Biol. Chem., 5600-5605, 275, 2000.

82

Monks A., Harris E.D., Vaigro-Wolff A., Hose C.D., Connelly J.W.,
Sausville E.A., UCN-01 enhances the in vitro toxicity of clinical
agents in human tumor cell lines, Invest. New Drugs, 95-107, 18,
2000.

83

Sato S., Fujita N., Tsuruo T., Interference with PDK1-Akt survival
signaling pathway by UCN-01 (7-hydroxystaurosporine), Oncogene,
1727-1738, 21, 2002.

84

Fuse E., Hashimoto A., Sato N., Tanii H., Kuwabara T., Kobayashi S.,
Sugiyama Y., Physiological modeling of altered pharmacokinetics of a
novel anticancer drug, UCN-01 (7-hydroxystaurosporine), caused by
slow dissociation of UCN-01 from human alpha1-acid glycoprotein,
Pharm. Res., 553-564, 17, 2000.

85

Kase H., Iwahashi K., Matsuda Y., K-252a, a potent inhibitor of

protein kinase C from microbial origin, J. Antibiot., 1059-1065, 39,
1986.

86

Akinaga S., Ashizawa T., Gomi K., Ohno H., Morimoto M., Murakata
C., Okabe M., Antitumor effect of KT6124, a novel derivative of
protein kinase K-252a, and its mechanism of action, Cancer
Chemother. Pharmacol., 266-272., 29, 1992.

87

Virchis A., Ganeshaguru K., Hart S., Jones D., Fletcher L., Wright F.,
Wickremasinghe R., Man A., Csermak K., Meyer T., Fabbro D.,

-167-

6:

Champain K., Yap A., Prentice H.G., Mehta A., A novel treatment
approach for low grade lymphoproliferative disorders using PKC412
(CGP41251), an inhibitor of protein kinase C, Hematol J., 131-136,
3, 2002.
88

Sielecki T.M., Boylan J.F., Benfield P.A., and Trainor G.L., Cyclindependent kinase inhibitors: Useful targets in cell cycle regulation, J.
Med. Chem., 2797-804, 43, 2000

89

Gibson A.E., Arris C.E., Bentley J., Boyle F.T., Curtin N.J., Davies
T.G., Endicott J.A., Golding B.T., Grant S., Grin R.J., Jewsbury P.,
Johnson L.N., Mesguiche V., Newell D.R., Noble M.E.M., Tucker J.A.,
Whiteld H.J., Probing the ATP ribose-binding domain of cyclindependent kinases 1 and 2 with O6-substituted guanine derivatives,
J. Med. Chem., 3381-3393, 45, 2002.

90

Soni R., O'Reilly T., Furet P., Muller L., Stephan C., Zumstein-Mecker
S., Fretz H., Fabbro D., Chaudhuri B., Selective in vivo and in vitro
effects of a small molecule inhibitor of cyclin-dependent kinase 4, J.
Natl. Cancer Inst., 436-446, 93, 2001.

91

Davies T.G., Bentley J., Arris C.E., Boyle F.T., Curtin J., Endicott J.A. ,
Gibson A.E., Golding B.T., Grin R.J., Hardcastle I.R., Jewsbury P.,
Johnson L.N., Mesguiche V., Newell D R., Noble M.E.M., Tucker J.A.,
Wang L., Whiteld H., Structure-based design of a potent purinebased cyclin-dependent kinase inhibitor, Nat. Struct. Biol., 745-749,
9, 2002.

92

Sayle K.L., Bentley J., Boyle F.T., Calvert A.H., Cheng Y., Curtin N.J.,
Endicott J.A., Golding B.T., Hardcastle I.R., et al, Structure-based
design
of
2-arylamino-4-cyclohexylmethyl-5nitroso-6aminopyrimidine inhibitors of cyclin-dependent kinases 1 and 2,
Bior. Med. Chem. Let., 3079-3082, 13, 2003.

93

Klutchko S.R., Hamby J.M., Boschelli D.H., Wu Z., Kraker A.J., Amar
A.M., Hartl B.G., Shen C., Klohs W.D., Steinkampf R.W., Driscoll D.L.,
et al., 2-Substituted aminopyrido[2,3-d]pyrimidin-7(8H)-ones.
Structure-activity relationships against selected tyrosine kinases and
in vitro and in vivo anticancer activity, J. Med. Chem., 3276-3292,
41, 1998.

94

Barvian M., Boschelli D.H., Cossrow J., Dobrusin E., Fattaey A.,
Fritsch A. et al., Pyrido[2,3-d]pyrimidin-7-one inhibitors of cyclindependent kinases, J. Med. Chem., 4606-4616, 43, 2000.

95

Rewcastle G.W., Denny W.A., Bridges A.J., Zhou H., Cody D.R.,
McMichael A., Fry D.W., Tyrosine kinase inhibitors. 5. Synthesis and
structure-activity relationships for 4-[(phenylmethyl)amino]- and 4(phenylamino)quinazolines as potent adenosine 5'-triphosphate
binding site inhibitors of the tyrosine kinase domain of the epidermal
growth factor receptor, J. Med. Chem., 3482-3487, 38, 1995.

96

Shewchuk L., Hassel A.l., Wisely B., Rocque W., Holmes W., Veal J.,
Kuyper L.F., Binding mode of the 4-anilinoquinazoline class of
protein kinase inhibitor: X-ray crystallographic studies of 4anilinoquinazolines bound to cyclin-dependent kinase 2 and p38
kinase, J. Med. Chem., 133-138, 43, 2000.

-168-

6:

97

Fry D.W., Kraker A.J., McMichael A., Ambroso L.A., Nelson J.M.,
Leopold W.R., Connors R.W., Bridges A.J., A specific inhibitor of the
epidermal growth factor receptor tyrosine kinase, Science, 10931095, 265, 1994.

98

Sielecki T.M., Johnson T.L., Liu J., Muckelbauer J.K., Grafstrom R. H.,
Cox S., et al., Quinazolines as cyclin dependent kinase inhibitors,
Bioorg. Med. Chem. Lett., 1157-1160, 11, 2001.

99

Zhu, Y.-P., and Woerdenbag H.J., Traditional

medicine, Pharm. World Sci., 103-112, 17, 1995.

100

Tang W. and Eisenbrand G., Chinese Drugs of Plant Origin:

Chemistry, Pharmacology, and Use in Traditional and Modern
Medicine, Springer-Verlag, Berlin, 1992.

101

Han R., Highlight on the studies of anticancer drugs derived from

plants in China, Stem Cells, 53-63 , 12, 1994.

102

Chinese Pharmacopoeia, Vol. 1, Peoples Health Publisher, Beijing,

1995.

103

Wu G.Y., Fang F.D., Liu J.Z., Chang A. and Ho Y.H., Studies on the
mechanism of action of indirubin in the treatment of chronic
granulocytic leukemia. I. Effects on nucleic acid and protein synthesis
in human leukemic cells, Chinese Med. J., 451-454 , 60, 1980.

104

Du D.J. and Ceng Q.T., Effect of indirubin on the incorporation of

isotope labeled precursors into nucleic acid and protein of tumor
tissues, Chinese Trad. Herb. Drugs, 406-409, 12, 1981.

105

Davies T.G., Tunnah P., Meijer L., Marko D., Eisenbrand G., Endicott
J.A., Noble M.E., Inhibitor binding to active and inactive CDK2. The
crystal structure of CDK2-cyclin A/indirubin-5-sulphonate, Structure,
389-397, 9, 2001.

106

Hoessel R., Leclerc S., Endicott J.A., Nobel M.E.M., n Lawrie A.,
Tunnah P., et al, Indirubin, the active constituent of a Chinese
antileukaemia medicine, inhibits cyclin-dependent kinases, Nat. Cell
Biol., 60-67, 1, 1999.

107

Killick R., Pollard C.C., Asuni A., Mudher A.K., Richardson J.C., et al.,
Presenilin 1 independently regulates -catenin stability and
transcriptional activity, J. Biol. Chem., 48554-48561, 276, 2001.

108

Kent L.L., Hull-Campbell N.E., Lau T., Wu J.C., Thompson S.A., Nori
M., Characterization of novel inhibitors of cyclin-dependent kinases,
Biochem. Biophys. Res. Commun., 768-774, 260, 1999.

109

Lane M.E., Yu B., Rice A., Lipson K.E., Liang C., Sun L., Tang C.,
McMahon G., Pestell R.G., Wadler S., A novel cdk2-selective
inhibitor, SU9516, induces apoptosis in colon carcinoma cells, Cancer
Res., 6170-6177, 61, 2001.

110

Fong T.A., Shawver L.K., Sun L., Tang C., App H., Powell T.J., Kim Y.
H., Schreck R., Wang X., Risau W., Ullrich A., Hirth K. P., McMahon
G., SU5416 is a potent and selective inhibitor of the vascular
endothelial growth factor receptor (Flk-1/KDR) that inhibits tyrosine
kinase catalysis, tumor vascularization, and growth of multiple tumor
types, Cancer Res., 99-106, 59, 1999.

-169-

chinese

herbal

6:

111

Kirkin V., Mazitschek R., Krishnan J., Steffen A., Waltenberger J.,
Pepper M.S., Giannis A., Sleeman J.P., Characterization of
indolinones which preferentially inhibit VEGF-C and VEGF-D-induced
activation of VEGFR-3 rather than VEGFR-2, Eur. J. Biochem., 55305540, 268, 2001.

112

Xiaoyuan L., Ping H., Jingrong J.C., Zhang J. and Cho T., Novel
Pyrrolyllactone and pyrrolyllactam indolinones as potent cyclindependent kinase 2 inhibitors, Bioorg. Med. Chem. Lett., 1939-1942,
13, 2003.

113

Sun,L., Tran N., TangF., App H., Hirth P., McMahon G., Tang C.,
Synthesis and biological evaluations of 3-substituted indolin-2-ones:
A novel class of tyrosine kinase inhibitors that exhibit selectivity
toward particular receptor tyrosine kinases, J. Med. Chem., 25882603, 41, 1998.

114

Sun L., Tran N., Liang C., Tang F., Rice A., Schreck R., Waltz,K.;
Shawver L.K., Mc Mahon G., Tang C., Design, synthesis, and
evaluations of substituted 3-[(3- or 4-carboxyethylpyrrol-2yl)methylidenyl]indolin-2-ones as inhibitors of VEGF, FGF, and PDGF
receptor tyrosine kinases, J. Med.Chem., 5120-5130, 42, 1999.

115

Sun L., Tran N., Liang C., Hubbard S., Tang F., Lipson K., Schreck R.,
Zhou Y., McMahon G., Tang C., Identification of substituted 3[(4,5,6,
7-tetrahydro-1H-indol-2-yl)methylene]-1,3-dihydroindol-2ones as growth factor receptor inhibitors for VEGF-R2 (Flk-1/KDR),
FGF-R1, and PDGF-Rbeta tyrosine kinases, J. Med.Chem., 26552663, 43, 2000.

116

Huang P., Ramphal J., Rice A., Tang F., Sun L., Liang C., Wei J.,
McMahon J., Tang C., Novel indolinone compounds as potent cyclindependent kinase 2 inhibitors, Abstract 3622, Proceedings of 92nd
Annual Meeting AACR, 2428 March 2001, New Orleans, LA, USA.

117

Zaharevitz D.W., Gussio R., Leost M., Senderowicz A.M., et al,

Discovery and initial characterization of the paullones, a novel class
of small-molecule inhibitors of cyclin-dependent kinases 1, Cancer
Res., 2566-2573, 59, 1999.

118

Schultz C., Link A., Leost M., Zaharevitz D.W., et al., Paullones, a
series of cyclin-dependent kinase inhibitors: Synthesis, evaluation of
CDK1/Cyclin B inhibition, and in vitro antitumor activity, J. Med.
Chem., 2909-2919, 42, 1999.

119

Schultz C., Lemcke T., Zaharevitz D.W., et al., 2-Substituted

Paullones:
CDK1/cyclin
B-inhibiting
property
and
in
vitro
antiproliferative activity, Biorg. Med. Chem. Lett., 567-571, 10,
2000.

120

Leost M., Schultz C., Link A., Wu Y.-Z., Biernat J., et al., Paullones
are potent inhibitors of glycogen synthase kinase 3 and cyclin
depedent kinase 5/p25, Eur. J. Biochem., 5983-5994, 267, 2000.

121

Knockaert M., Wieking K., Schmitt S., Leost M., Targets of Paullones
identification following affinity purification on immobilized inhibitor,
J. Biol. Chem., 25493-25501, 277, 2002.

-170-

6:

122

Lahusen T., De Siervi A., Kunick C., Senderowicz A.M.,

Alsterpaullone, a novel cyclin-dependent kinase inhibitor, induces
apoptosis by activation of caspase-9 due to perturbation in
mitochondrial membrane potential, Mol. Carcinogen., 183-194, 36,
2003.

123

Kunick C., Lauenroth K., Leost M., Meijerc L., Lemckeb T., 1Azakenpaullone is a selective inhibitor of glycogen synthase kinase3, Biorg. Med. Chem. Lett., 413-416, 14, 2004.

124

Roll D.M., Ireland C.M., Lu H.S.M., Clardy J., Fascaplysin, an

unusual
antimicrobial
pigment
from
the
marine
sponge
fascaplysinopsis sp., J. Org. Chem., 3276-3279, 53, 1988.

125

Soni R., Muller L., Furet P., Schoepfer J., Stephan C., ZumsteinMecker S., Fretz H., Chaudhuri B., Inhibition of cyclin-dependent
kinase 4 (Cdk4) by Fascaplysin, a marine natural product, Biochem.
Biophys. Res. Comm., 877-884, 275, 2000.

126

Horman A., Chaudhuri B., Frentz H., DNA binding properties of the
marine sponge pigment Fascaplycin, Biorg. Med. Chem., 917-920, 9,
2001.

127

Cimino G., De Rosa S., De Stefano S., Mazzarella L., Puliti R., and
Sodano G., Isolation and x-ray crystal structure of a novel bromo
compound from two marine sponges, Tet. Lett., 767-768, 23, 1982.

128

Kitagawa I., Kobayashi M., Kitanaka K., Kido M., and Kyogoku Y.,
Marine natural products. XII. On the chemical constituents of the
okinawan marine sponge hymeniacidon aldis., Chem. Pharm. Bull.,
2321-2328, 31, 1983.

129

De Nanteuil G., Ahond A., Guilhem J., Poupat C., Tran Huu Dau E.,
Potier P., Pusset M., Pusset J., and Laboute P. Marine invertebrates
from the new caledonian lagoon. V. Isolation and identification of
metabolites of a new species of sponge, Pseudaxinyssa cantharella,
Tet. Lett., 60196033, 41, 1985.

130

Schmitz F.J., Gunasekera S.P., Lakshmi V., and Tillekeratne L.M.V.,

Marine natural products: Pyrrololactams from several sponges, J.
Nat. Prod., 47-53, 48, 1985.

131

Pettit G.R., Herald C.L., Leet J.E., Gupta R., Schaufelberger D.E.,
Bates R.B., Clewlow P.J., Doubek D.L., Manfredi K.P., Rutzler K., et
al., Antineoplastic agents. 168. Isolation and structure of
axinohydantoin, Can. J. Chem., 1621-1624, 68, 1990.

132

Meijer L., Thunnissen A.-M.W.H., White A.W., Garnier M., et al.,

Inhibition of cyclin-dependent kinases, GSK-3b and CK1 by
hymenialdisine, a marine sponge constituent, Chem. Biol., 51-57, 7,
2000.

133

Tasdemir D., Mallon R., Greenstein M., Feldberg L., Kim S., et al.,
Aldisine alkaloids from the philippine sponge stylissa massa are
potent inhibitors of mitogen-activated protein kinase kinase-1 (MEK1), J. Med. Chem., 529-532, 45, 2002.

134

Wan Y., Hur W., Cho C., Liu Y., Adrian F., Lozach O., et al.,
Synthesis and target identification of hymenialdisine analogs,
Chem. Biol., 247-251, 11, 2004.

-171-

6:

135

Kubo A., Nakagawa K., Varma R.K., Conrad N.K., Cheng J.Q., Lee W.
C., Testa J.R., Johnson B.E., et al., The p16 status of tumor cell lines
identifies small molecule inhibitors specific for cyclin-dependent
kinase 4, Clin. Cancer Res., 4279-4286, 5, 1999.

136

Antonini I., Polucci P., Jenkins T.C., Kelland L.R., Menta E., Pescalli
N., Stefanska B., Mazerski J., Martelli S., J. Med. Chem., 3749-3755,
40, 1997.

137

Honma T., Hayashi K., Aoyama T., Hashimoto N., Machida T., et al.,
Structure-Based generation of a new class of potent Cdk4 inhibitors:
New de novo design strategy and library design, J. Med. Chem.,
4615-4627, 44, 2001.

138

Honma T., Yoshizumi T., Hashimoto N., Hayashi K., Kawanishi N., et
al., A novel approach for the development of selective Cdk4
inhibitors: Library design based on locations of Cdk4 specific amino
acid residues, J. Med. Chem., 4628-4640, 44, 2001.

139

Ikuta M., Kamata K., Fukasawa K., Honma T., Machida T., et al.,
Crystallographic approach to identification of cyclin-dependent
kinase 4 (CDK4)-specific inhibitors by using CDK4 mimic CDK2
protein, J. Biol. Chem., 27548-27554, 276, 2001.

-172-

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-185-

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-

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-187-

7:

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,
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DNA 88 .

-188-

7:

Goodsell D.S., The molecular perspective: DNA topoisomerases,

Oncologist, 381-382, 7, 2002.

Changela A., Perry K., Taneja B. and Mondragn A., DNA

manipulators: Caught in the act, Curr. Opin. Struct. Biol., 15-22, 13,
2003.

Wang J.C., Interaction between DNA and an Escherichia coli protein

, J. Mol. Biol., 523-533, 55, 1971.

Wang J.C., DNA topoisomerases, Annu. Rev. Biochem., 635-692,

65, 1996.

Nitiss J.L., Investigating the biological functions of DNA

topoisomerases in eukaryotic cells, Biochim. Biophys. Acta, 63-81,
1400, 1998.

Bailly C., Homocamptothecins: Potent topoisomerase I inhibitors and

promising anticancer drugs, Crit. Rev. Oncol. Hemat., 91-108, 45,
2003.

Gimenez-Albian J.F., Clarke D.J., Mullinger A.M., Downes C.S.,

Johnson R.T., A postprophase topoisomerase II-dependent
chromatid core separation step in the formation of metaphase
chromosomes, J. Cell Biol., 7-17, 131, 1995.

Rowe T.C., Tewey K.M., Liu L.F., Identification of the breakagereunion subunit of T4 DNA topoisomerase, J. Biol. Chem., 91779181, 259, 1984.

Tse-Dinh Y.C., Wang J.C., Complete nucleotide sequence of the topA

gene encoding Escherichia coli DNA topoisomerase I, J. Mol. Biol.,
321-331, 191, 1986.

10

Trucksis M., Depew R.E, Identification and localization of a gene that

specifies production of Escherichia coli DNA topoisomerase I, Proc.
Natl. Acad. Sci. USA, 2164-2168, 78, 1981.

11

Kirkegaard K., Pflugfelder G., Wang J.C., Cold Spring Harb. Sym.,
Cold Spring Harb. Symp. Quant. Biol., 411-419, 49, 1984.

12

Masse E., Drolet M., Relaxation of transcription-induced negative

supercoiling is an essential function of Escherichia coli DNA
topoisomerase I, J. Biol. Chem., 16654-16658, 274, 1999.

13

Grishin N.V., C-terminal domains of Escherichia coli topoisomerase I

belong to the zinc-ribbon superfamily, J. Mol. Biol., 1165-1177, 299,
2000.

14

Digate R.J., Marians K.J., Molecular cloning and DNA sequence

analysis of Escherichia coli topB, the gene encoding topoisomerase
III, J. Biol. Chem., 17924-17930, 264, 1989.

15

Hiasa H., Marians K.J., Topoisomerase III, but not topoisomerase I,

can support nascent chain elongation during theta-type DNA
replication, J. Biol. Chem., 32655-32659, 269, 1994.

16

Levine C., Hiasa H., Marians K.J., DNA gyrase and topoisomerase IV:
biochemical activities, physiological roles during chromosome

-189-

7:

replication, and drug sensitivities, Biochem. Biophys. Acta , 29-43,

1400, 1998.
17

Peng H., Marians K.J., The interaction of Escherichia coli

topoisomerase IV with DNA, J. Biol. Chem., 25286-25290, 270,
1995.

18

Khodursky A.B., Peter B.J., Schmid M.B., DeRisi J., Botstein D.,
Brown P.O., Cozzarelli N.R., Analysis of topoisomerase function in
bacterial replication fork movement: use of DNA microarrays, Proc.
Natl. Acad. Sci. USA, 9419-9424, 97, 2000.

19

Zechiedrich E.L, Khodrusky A.B., Bachellier S., Schneider R., Chen D.,
Lilley D.M., Cozzarelli N.R., Roles of topoisomerases in maintaining
steady-state DNA supercoiling in Escherichia coli, J. Biol. Chem.,
8103-8113, 275, 2000.

20

Juan C., Wang J., Liu A.A., Whang-Peng J., Knutsen T., Huebner K.,
Croce C.M., Zhang H., Wang J.C., Liu L.F., Human DNA
topoisomerase I is encoded by a single-copy gene that maps to
chromosome region 20q12-13.2, Proc. Natl. Acad. Sci. USA, 89108913, 85, 1988.

21

Kunze N., Yang G., Dolberg M., Sundarp R., Knippers R., Richter A.,
Structure of the human type I DNA topoisomerase gene, J. Biol.
Chem., 9610-9616, 266, 1991.

22

Pommier Y., Pourquier P., Fan Y., Strumberg D., Mechanism of

action of eukaryotic DNA topoisomerase I and drugs targeted to the
enzyme, Biochem. Biophys. Acta, 83-105, 1400, 1998.

23

Wallis J.W., Chrebet G., Brodsky G., Rolfe M., Rothstein R., A hyperrecombination mutation in S. cerevisiae identifies a novel eukaryotic
topoisomerase, Cell, 409-419, 58, 1989.

24

Kim R., Wang J.C., Identification of the yeast TOP3 gene product as
a single strand-specific DNA topoisomerase, J. Biol. Chem., 1717817185, 267, 1992.

25

Kawasaki K., Minoshima S., Nakato E., Shibuya K., Shintani A.,
Schmeits J.L., Wang J., Shimizu N.J., One-megabase sequence
analysis of the human immunoglobulin gene locus, Genome Res.,
250-261, 7, 1997.

26

Li W., Wang J.C., Mammalian DNA topoisomerase III is essential in

early embryogenesis, Proc. Natl. Acad. Sci. USA, 1010-1013, 95,
1998.

27

Gangloff S., de Massey B., Arthur L., Rothstein R., Fabre F., The
essential role of yeast topoisomerase III in meiosis depends on
recombination, EMBO J., 1701-1711, 18, 1999.

28

Shimamoto A., Nishikawa K., Kitao S., Furuichi Y., Human RecQ5, a
large isomer of RecQ5 DNA helicase, localizes in the nucleoplasm and
interacts with topoisomerases 3 and 3, Nucleic Acids Res., 16471655, 28, 2000.

29

Wu L., Davies S.L., North P.S., Goulaouic H., Riou J., Turley H.,
Gatter K.C., Hickson I.D., The Bloom's syndrome gene product

-190-

7:

interacts with topoisomerase III, J. Biol. Chem., 9636-9644, 275,

2000.
30

Drake F.H., Hofmann G.A., Bartus H. F., Mattern M.R., Crooke S.T.,
Mirabelli C.K., Biochemical and pharmacological properties of p170
and p180 forms of topoisomerase II. Biochemistry, 8154-8160, 28,
1989

31

Tsai-Pflugfelder M., Liu L.F., Liu A.A., Tewey K.M., Whang-Peng J.,
Knutsen T., Huebner K., Croce C.M., Wang J.C., Cloning and
sequencing of cDNA encoding human DNA topoisomerase II and
localization of the gene to chromosome region 17q21-22, Proc. Natl.
Acad. Sci. USA, 7177-7181, 85, 1988.

32

Tan K.B., Dorman T.E., Falls K.M., Chung T.D., Mirabelli C.K., Crooke
S.T., Mao J., Topoisomerase II and topoisomerase II genes:
characterization and mapping to human chromosomes 17 and 3,
respectively, Cancer Res., 231-234, 52, 1992.

33

Sng J.H., Heaton V.J., Bell M., Maini P., Austin C.A., Fisher L.M.,
Molecular cloning and characterization of the human topoisomerase
II and II genes: evidence for isoform evolution through gene
duplication, Biochem. Biophys. Acta, 395-406, 1444, 1999.

34

Earnshaw W.C., Halligan B., Cooke C.A., Heck M.M., Liu L.F.,
Topoisomerase II is a structural component of mitotic chromosome
scaffolds, J. Cell Biol., 1706-1715, 100, 1985.

35

Yang X, Li W, Prescott ED, Burden S J; Wang J C, DNA

topoisomerase II and neural development, Science, 131-134, 287,
2000.

36

Wang Y., Knudsen B.R., Bjergback L., Westergaard O., Andersen

A.H., Stimulated activity of human topoisomerases II and II on
RNA-containing substrates, J. Biol. Chem., 22839-22846, 274,
1999.

37

Sullivan DM, Latham MD, Ross WE, Proliferation-dependent

topoisomerase II content as a determinant of antineoplastic drug
action in human, mouse, and Chinese hamster ovary cells, Cancer
Res., 3973-3979, 47, 1987.

38

Liu L.F., DNA topoisomerase poisons as antitumor drugs, Annu.

Rev. Biochem., 351-375, 58, 1989.

39

Burden AD, Osheroff N., Mechanism of action of eukaryotic

topoisomerase II and drugs targeted to the enzyme, Biochem.
Biophys. Acta, 139-154, 1400, 1998

40

Zucker RM, Adams DJ, Bair KW, Elstein KH, Polyploidy induction as a
consequence of topoisomerase inhibition. A flow cytometric
assessment, Biochem. Pharmacol., 2199-2208, 42, 1991

41

Sumner A.T., Induction of diplochromosomes in mammalian cells by

inhibitors of topoisomerase II, Chromosoma, 486-490, 107, 1998.

42

Capranico G., Binaschi M., DNA sequence selectivity of

topoisomerases and topoisomerase poisons, Biochem. Biophys. Acta,
185-194, 1400, 1988.

-191-

7:

43

Thompsen B., Mollerup S., Bonven B.J., et al., Sequence specificity

of DNA topoisomerase I in the presence and absence of
camptothecin, EMBO J., 1817-1823, 6, 1987.

44

Yang Z, Champoux JJ., The role of histidine 632 in catalysis by

human topoisomerase I, J. Biol. Chem., 677-685, 276, 2001.

45

Krogh S., Mortensen U.H., Westergaard O., Bonven B.J., Eukaryotic

topoisomerase I-DNA interaction is stabilized by helix curvature,
Nucleic Acids Res., 1235-1241, 19, 1991.

46

Leteurtre F., Kohlhagen G., Fesen M.R., Tanizawa A., Kohn K.W.,
Pommier Y., Effects of DNA methylation on topoisomerase I and II
cleavage activities, J. Biol. Chem., 7893-7900, 269, 1994.

47

Champoux J.J., DNA is linked to the rat liver DNA nicking-closing

enzyme by a phosphodiester bond to tyrosine, J. Biol. Chem., 48054809, 256, 1981.

48

Lynn R.M., Bjornsti M.A., Caron P.R., Wang J.C., Peptide sequencing
and site-directed mutagenesis identify tyrosine-727 as the active site
tyrosine of Saccharomyces cerevisiae DNA topoisomerase I, Proc.
Natl. Acad. Sci. USA, 3559-3563, 86, 1989.

49

Christiansen K., Svejstrup A.B., Andersen AH, Westergaard O.,

Eukaryotic topoisomerase I-mediated cleavage requires bipartite
DNA interaction. Cleavage of DNA substrates containing strand
interruptions implicates a role for topoisomerase I in illegitimate
recombination, J. Biol. Chem., 9690-9701, 268, 1993.

50

Tanizawa A., Kohn K.W., Pommier Y., Induction of cleavage in

topoisomerase I c-DNA by topoisomerase I enzymes from calf thymus
and wheat germ in the presence and absence of camptothecin,
Nucleic Acids Res., 5157-5166, 21, 1993.

51

Pourquier P., Ueng L.M., Kohlhagen G., Mazumder A., Gupta M., Kohn
K.W., Pommier Y., Effects of uracil incorporation, DNA mismatches,
and abasic sites on cleavage and religation activities of mammalian
topoisomerase I, J. Biol. Chem., 7792-7796, 272, 1997.

52

Pourquier P., Pilon A.A., Kohlhagen G., Mazumder A., Sharma A.,
Pommier Y., Trapping of mammalian topoisomerase I and
recombinations induced by damaged DNA containing nicks or gaps.
Importance of DNA end phosphorylation and camptothecin effects, J.
Biol. Chem., 26441-26447, 272, 1997.

53

Stivers J., Harris T.K., Mildvan A.S., Vaccinia DNA Topoisomerase I:

Evidence supporting a free rotation mechanism for DNA supercoil
relaxation, Biochemistry, 5212-5222, 36, 1997.

54

Christiansen K., Knudsen B.R., Westergaard O., The covalent

eukaryotic topoisomerase I-DNA intermediate catalyzes pHdependent hydrolysis and alcoholysis. J. Biol. Chem., 11367-11373,
269, 1994.

55

Yang S.W., Burgin A.B. Jr., Huizenga B.N., Robertson C.A., Yao K.C.,
Nash H.A., A eukaryotic enzyme that can disjoin dead-end covalent
complexes between DNA and type I topoisomerases, Proc. Natl.
Acad. Sci. USA, 11534-11539, 93, 1996.

-192-

7:

56

Shuman S., Novel approach to molecular cloning and polynucleotide

synthesis using vaccinia DNA topoisomerase, J. Biol. Chem., 3267832684, 269, 1994.

57

Chen A.Y., Liu L.F., DNA topoisomerases: essential enzymes and

lethal targets. Annu. Rev. Pharmacol. Toxicol., 191-218, 218, 1994.

58

Christiansen K., Westergaard O., Characterization of intra- and

intermolecular DNA ligation mediated by eukaryotic topoisomerase I.
Role of bipartite DNA interaction in the ligation process, J. Biol.
Chem., 721-729, 269, 1994.

59

Been M.D., Burgess R.R., Champoux J.J., Nucleotide sequence

preference at rat liver and wheat germ type 1 DNA topoisomerase
breakage sites in duplex SV40 DNA, Nucleic Acids Res., 3097-3114,
12, 1984.

60

Redinbo M.R., Stewart L., Kuhn P., Champoux J.J., Hol W.G.J.,
Crystal structures of human topoisomerase I in covalent and
noncovalent complexes with DNA, Science, 1504-1513, 279, 1998.

61

Redinbo M.R., Champoux J.J., Hol W.G.J., Novel insights into

catalytic mechanism from a crystal structure of human topoisomerase
I complex with DNA, Biochemistry, 6832-6840, 39, 2000.

62

Chillemi G., Castrignano T., Desideri A., Structure and hydration of

the DNA-human topoisomerase I covalent complex, Biophys. J., 490500, 81, 2001.

63

Capranico G., Jaxel C., Roberge M., Kohn K.W., Pommier Y.,
Nucleosome positioning as a critical determinant for the DNA
cleavage sites of mammalian DNA topoisomerase II in reconstituted
simian virus 40 chromatin, Nucleic Acids Res., 4553-4559, 18, 1990.

64

Kreuzer K.N., Alberts B.M., Site-specific recognition of bacteriophage

T4 DNA by T4 type II DNA topoisomerase and Escherichia coli DNA
gyrase, J. Biol. Chem., 5339-5346, 259, 1984.

65

Javaherian K., Liu L.F., Association of eukaryotic DNA topoisomerase

I with nucleosomes and chromosomal proteins, Nucleic Acids Res.,
461-472, 11, 1983.

66

Srivenugopal K.S., Morris D.R., Differential modulation by

spermidine of reactions catalyzed by type 1 prokaryotic and
eukaryotic topoisomerases, Biochemistry, 4766-4771, 24, 1985.

67

Kroeger P.E., Rowe T.C., Analysis of topoisomerase I and II cleavage

sites on the Drosophila actin and Hsp70 heat shock genes,
Biochemistry, 2492-2501, 31, 1992.

68

Stewart A.F., Herrera R.E., Nordheim A., Rapid induction of c-fos

transcription reveals quantitative linkage of RNA polymerase II and
DNA topoisomerase I enzyme activities, Cell, 141-149, 60, 1990.

69

Wang J.C., Lynch A.S., Transcription and DNA supercoiling, Curr.

Opin. Gene Dev., 764-768, 3, 1993.

70

Merino A., Madden K.R., Lane W.S., Champoux J.J., Reinberg D.,
DNA topoisomerase I is involved in both repression and activation of
transcription, Nature, 227-242, 365, 1993.

-193-

7:

71

Pommier Y., Jenkins J., Kohlhagen G., Leteurtre F., DNA

recombinase activity of eukaryotic DNA topoisomerase I; effects of
camptothecin and other inhibitors, Mut. Res., 135-145, 337, 1995.

72

Wang H.P., Rogler C.E., Topoisomerase I-mediated integration of

hepadnavirus DNA in vitro, J. Virol., 2381-2392, 65, 1991.

73

Castano I.B., Brzoska P.M., Sadoff B.U., Chen H., Christman M.F.,
Mitotic chromosome condensation in the rDNA requires TRF4 and
DNA topoisomerase I in Saccharomyces cerevisiae, Genes Dev.,
2564-2576, 10, 1996.

74

Subramanian D., Rosenstein B.S., Muller M.T., Ultraviolet-induced

DNA damage stimulates topoisomerase I-DNA complex formation in
vivo: Possible relationship with DNA repair, Cancer Res., 976, 58,
1998.

75

Lanza A., Tornaletti S., Rodolfo C., Scanavini M.C., Pedrini A.M.,
Human DNA topoisomerase I-mediated cleavages stimulated by
ultraviolet light-induced DNA damage, J. Biol. Chem., 6978-6986,
271, 1996.

76

Heiland S., Knippers R., and Kunze N., The promoter region of the
human type-I-DNA-topoisomerase gene. Protein-binding sites and
sequences involved in transcriptional regulation, Eur. J. Biochem.,
813-822, 217, 1993.

77

Romig H., Richter A., Expression of the type I DNA topoisomerase

gene in adenovirus-5 infected human cells, Nucleic Acids Res., 801808, 18, 1990

78

Tse-Dinh Y.C., Wong T.W., Goldberg A.R., Virus- and cell-encoded

tyrosine protein kinases inactivate DNA topoisomerases in vitro,
Nature, 785-786, 312, 1984.

79

Pommier Y., Kerrigan D., Hartman K.D., Glazer R.I., Phosphorylation

of mammalian DNA topoisomerase I and activation by protein kinase
C, J. Biol. Chem., 9418-9422, 16, 1990.

80

Cardellini E., Durban E., Phosphorylation of human topoisomerase I

by protein kinase C in vitro and in phorbol 12-myristate 13-acetateactivated HL-60 promyelocytic leukaemia cells, Biochem. J, 303-307,
291, 1993.

81

Kasid U.N.,Halligan B., Liu L.F., Dritschilo, Smulson M., Poly(ADPribose)-mediated post-translational modification of chromatinassociated human topoisomerase I. Inhibitory effects on catalytic
activity, J. Biol. Chem., 18687-18692, 264, 1989.

82

Park J.K., Kim W.J., Park Y.S., Choi H.S., Yu J.E., Han D.M., Park
S.D., Inhibition of topoisomerase I by NAD and enhancement of
cytotoxicity of MMS by inhibitors of poly(ADP-ribose) polymerase in
Saccharomyces cerevisiae, Cell Mol. Biol., 739-744, 37, 1991.

83

Mattern M.R., Mong S.M., Bartus H.F., Mirabelli C.K.,Crooke S.T.,

Johnson R.K., Relationship between the intracellular effects of
camptothecin and the inhibition of DNA topoisomerase I in cultured
L1210 cells, Cancer Res., 1793-1798, 47, 1987.

-194-

7:

84

Rose K.M., Szopa J., Han F.S., Cheng Y.C., Richter A., Scheer U.,
Association of DNA topoisomerase I and RNA polymerase I: A
possible role for topoisomerase I in ribosomal gene transcription,
Chromosoma, 411-416, 96, 1988.

85

Gobert C., Bracco L., Rossi F., Olivier M., Tazi J., Lavelle F., Larsen
A.K., Riou J.F., Modulation of DNA topoisomerase I activity by p53,
Biochemistry, 5778-5786, 35, 1997.

86

Ciavarra R.P., Goldman C., Wen K.K., Tedeschi B., Castora F.J., Heat
stress induces hsc70/nuclear topoisomerase I complex formation in
vivo: Evidence for hsc70-mediated, ATP-independent reactivation in
vitro, Proc. Natl. Acad. Sci. USA, 1751-1755, 91, 1994.

87

Haluska P. Jr, Saleem A., Edwards T.K., Rubin E.H., Interaction

between the N-terminus of human topoisomerase I and SV40 large T
antigen, Nucleic Acids Res., 1841-1847, 26, 199.

88

Shyamal D.D., Leroy F.L., Vazquez-Abad D., D'Arpa P., Ubiquitindependent Destruction of Topoisomerase I Is Stimulated by the
antitumor drug camptothecin, J. Biol. Chem., 24159-24164, 272,
1997.

-195-

7:

topo I ,
.
topo I. topo I
, topo I .

. ,
topo I topo I 1 ,

topo I. ,
topo I.
,

DNA,

topo I
(CPTs)
(camptothecin, CPT)
1958
Camptotheca acuminata,
,
2 .
1966 3 .
CPT

(CPT-Na)

1970. , CPT-Na,

-196-

8:

, 4 .
, ,

, . ,
1985, CPT topo I

topotecan

(Hycamptin)

irinotecan

(Camptostar) FDA
.
9
10
11

B
13

N
1

5
4

C N
D

2 3
12
14 15
18
19

16a
16 17

N
N

E O
20

O
OH

21

Camptothecin
CPT

CPT-Na

N
N

O
O

HO

N
O

Irinotecan

Topotecan

42. CPT .
.
.
CPTs ,

---

C-20.
20S- 10-100 20R 5 ,

C-9 C-10 6 .

CPTs.
. pH,

-197-

7:

pH 7 . ,
pH .
10
8 . ,

pH 7.4 8.
,

,

.

, 1- , ,
.
.


CPT .
CPT DNA
,
S 9 . ,
CPT
DNA ,
DNA- CPT 10 .
T

S
DNA
DNA topo I
11 .

topo I-DNA CPT,

CPT,

topo

I 12 .

CPT

DNA-topo I,

-198-

8:

. CPT
DNA topo I 13 , CPT

. ,
CPT
topo I-DNA
,
14 . ,
(triplex-forming oligonucleotides)
CPTs 15
DNA
topo I
CPT topo I-DNA.

CPT topo I-DNA. Hol 16 ,
CPT

+1

(Stacking)

180
Watson Crick. Pommier 17 , CPT



DNA.

Kerrigna

Plich 18

, -
,
. , Pommier

7-ethyl-10-hydroxyCPT (SON-38), topo
I , DNA 19 . , +1
DNA, CPT ,
,
20- .

-DNA-.
CPT,

-199-

7:

topo I,
CPT.
Arg364, Asn722 Lys532
CPT 20- 21 - 22 .
CPT
,
van der Waals. docking CPT

topo I-DNA
-.

G+1

HO

""

""
T-1

A
O

HO
O

Asn 722
-1

Asn 352
O

HN

N
O

NH2
- 1

N
N
DNA

N
N

H
H O

DNA

O
H

Lys 532
Asp 533

Arg 364

43.
SN-38 DNA.

CPT.
CPT topo I-DNA
topo I

-200-

8:

DNA S
11. topo I
, ,
CPT 23 .
T

DNA 24 . CPT

.
CPT-topo I

CPT

CPT
. CPT
(small ubiquitin modifiers, SUMO)
topo I,
26S 25-26 .

topo I.
DNA
topo I 27 , CPT topo I,

DNA. ,

Trf4p
CPT, Trf4p
DNA CPT 28 .
, CPT
,

topo

I,

29

.
- CPTs.
-

.
,
,

-201-

7:

DNA .

:
`

A, B, C D
in vivo in vitro CPTs.

,
,

S C-20,
CPT
30 .

(/) .
.

,
CPT 31 .
T

, topotecan
irinotecan,
. , , C-11 12
32,33 . , 10,11-, 10,11, 11-F 11-CN topo I
30, 34 .
2, , 9 10
L1210122.
9-NH2-CPT (CPT-1) 9-N2-CPT (rubitecan) in
vivo rubitecan

.
7,9,10 11
topo I
CPT,

-202-

8:

. C-10
,
CPT
.
irinotecan in vivo SN-38 ,
, topo I-DNA 35 .

C-7

10,11-()CPT.

Lurtotecan

36 , CPT-2,

Exatecan 28-
topotecan . ,
, Silatecans,

DB-67,

CPT in vivo .
37 .
,
CPT. ,
C-7 -
CPT-3

38 .

-203-

7:

NCH3

NH2

NO2

N
N

CPT-1

O
O

OH O

Rubitecan

N
O
Lutrotecan

OH O

OH O

N
Cl

NH2

OH O

O
CPT-2

O
N

N
O

Si tBu
HO

Exatecan

OH O

DB-67

OH O

CH NOC(CH3)3
O
N
N
O
CPT-3

OH O

44. CPT (/)

.

C/D . C D
. CPT-4
CPT-5 topo I-DNA
39 . deaza- CPT-6 60 topo I 40 .
,
C-5 D-14. C-5 (
5-, 5-, 5-) 5- 5-hydromethylCPT
(CPT-7 CPT-8 ) 41,

42

CPT-9 C-5 2-fluoroethylester

CPT-10 (ethylidene CPT) in vitro
43 , CPT
P388 44 .

-204-

8:

NO2
N

HN
N

N
CPT-4

HO

O
CPT-5

CPT-6

OH O

OH O

CH2OH
O
N

OCH2CH2F
O

O
N

N
O

CPT-7, OH O
CPT-8,

O
CPT-9

CPT-10

OH O

OH O

45. CPT C/D.

E . CPT11, CPT-12, CPT-13 CPT-14,

topo I8. ,

CPT-15

CPT-16,

,
topo I8. , , S
C-20. 20-
topo I.
CPT-17 (20-aminoCPT) topo I
pH, 20-2

,
,
20- CPT 7. 20-deoxy CPT-18

topo

8.

CPTs, CPT-19 CPT-20,

,

. -hydroxylactone
-hydroxylactone CPT-21

-205-

7:

HomoCPT, topo I
45 .
-80915 (10,11-difluorohomoCPT)

46 . 7-(tert-butyl-dimethylsilyl)
CPT-22
, Du1441
--
topo I 47 . ,
-
topo I,

topo I 48,49 .
O

N
N

CPT-13

CPT-14

OH O

OH O

N
O

CPT-15

CPT-16

O
O

HO

CPT-17

H2N

CPT-18 X=H
CPT-19 X=Cl
CPT-20 X=Br

tBu
Si

N
N
O

BN-80915

HO

N
N

O
O

CPT-22

O
HO

Du1441

HO

46 . CPT .

CPT .
Topotecan. CPT
FDA. C-9.
in vitro 6.

-206-

N
O

CPT-21
HO
Homo-CPT

N tBu

OH OH

NH
CPT-12

OH O

NH
CPT-11

8:

,
50, 51 , 52 .

.
53 ,

. , topotecan
,
54 .
Irinotecan149.
CPT .
1980,
. 1994
( -),
. 1995, (
topotecan),
,. 1996

, fluorouracil.
9-aminocamptothecin (CPT-1).

55 . ,

56,

57

. ,

9-aminocamptothecin .
9-nitrocamptothecin

(Rubitecan).

p.o. .

,
CPT . 58 .

59,

60

,
8 % 61 .

-207-

7:

,
.
Exatecan. CPT
.

,

62

.
63 ,

64,

65

. ,

gemcitabine
gemcitabine.

Paecilomyces sp.

66

saintopin

topo I. saintopin

topo I.
topo I 67 . saintopin UCE1022
, DNA
UCE6 saintopin 66,67. saintopin CPT
topo I 68 .
O

HO

OH

OH O

HO

OH OH

OH O

Saintopin

OH OH O

Saintopin E

HO

OH

OH O

OH

HO

O
S
OH
O

OH O

OH

OH O

OH

OH
O

UCE 1022

UCE 6

47. .

-208-

8:

nitidine,

Zanthoxyulum nitidum
fagorinide,

aznthoxyloides

Lam.,

Fagarara

topo I
DNA 69, 70 , 71 . H O-methyl-fagaronine,
isofagaridine, fagaridine chelerytrine
DNA69,70.

topo I.

topo I. nitidines

72 .
protoberberine, coralyne,
73
5,6-dihydrocoralyne (D-coralyne)

topo I. ,
74 . DNA
nitidine coralyne CPT 75
T

74

. coralyne 5
CPT DNA
topo I, CPT/K5
CPT75.

protoberberine

76

-209-

7:

CH3O

CH3O
N

CH3O

CH3O

Nitidine

O-methyl-fararonine

HO

Fagaridine

CH3O

OCH3

OH

CH3O

Fagaronine

CH3O

CH3O

OCH3

Lisofagaridine

Chelerytrine

48.
.

topo I intoplicine
77 .

DNA topo I .
, AzaIQD
topo I
GAL1, topo I
AzaIQD 78 . intoplicine, o AzaIQD
DNA

DNA.
wakayin, -,

Clavelina

sp.,

DNA

topo I
CPT 79 . ,
T

DNA. wakayin
CPT 79.

-210-

8:

(CH3)3

HN

H
N

N
OCH3

N
N

N
H

AZAIQD

H
N

intoplicine

H
N

CH3O
NH

CH3O
O

wakayin

NSC 314622

49. topo I.
NSC 314622 NCI
COMPARE saintopin 80 .
NSC 314622 DNA topo I
,
CPT. NSC 314622
CPT,
. NSC 314622
DNA, NSC 314622

DNA

MCF7

DNA

CPT.
CEM/C2,
CPT topo I,
NSC 31462220, 81 .

. ,
indolo[2,3-a]carbazoles.

, ,

, .

-211-

7:

Rebeccamycin

rebeccamycin

1985 Saccharothix aerocolonigenes (

Nocardia aerocolonigenes).
82,

rebeccamycin

83

, staurosporine, o AT2433 A1
1 84 ,
. 30 L
663 mg/L rebeccamycin

staurosporine K-252a

,
.

. staurosporine

rebeccamycin

topo I, PKC
PKA 85 .

H
N

O
H
N

N
R

OH

N
H

N
R

OH

HO
CH3O

OH

CH3O
CH3HN

Rebeccamycin, R = Cl
DBrIC, R = Br

H
N

N
H

OH

N
H

H3CO

OH
AT2433 A1, R = Cl
AT2433 B1, R = H

HO

NHCH3

N
H

COOCH3
K-252a

Staurosporine

50. .

1987,

rebeccamycin

8 256 mg/ Kg

P388

L1210

86

. DNA,

-212-

8:

. , 11dechlororebeccamycin 87,88
86. 1991 ,
NaBr NaCl,
bromorebeccamycin (DrIC) 89 . DrIC
rebeccamycin
89, 90 .

rebeccamycin.

Grignard)

Kaneko

7-

,
84.
Diels-Alder
2,2- 7,7-85.
,
Danisshefsky
1,2- 91 .
Faul
7--3- -3- . 92 .

-213-

O
Cl

N
H

Br

7:

CH2OBn
N
O

AcO

CH2OBn
N
O

Br

N
H

Cl

Kaneko et al.

N
H

Cl

Kaneko et al.

CH2OBn
N
O

N
H

Cl

N
H

Cl

OAc

CH3O
AcO

AcO

Br

H
N

N
Cl

OH

N
H

Cl

HO
Danishefsky
CH3O

Rebeccamycin

CH2OBn
N
O

Faul et al.

OH

NH2
O

Cl

N
H

N
SEM

CH3O

OBn

N
Cl

Cl

OH

BnO
CH3O

BnO

OBn

CH3O

O
N
H

Cl

51.
rebeccamycin.


rebeccamycin

.

-214-

8:

rebeccamycin
.

rebeccamycin,
1,11-dechorinated rebeccamycin
85,89, 93 , 94 .
topo I DNA,
DNA
DNA.
topo I,
DNA.
Cl topo I,

topo I 95 .
,

DNA,
DNA .

DNA,

TpG
Got. ,
DNA
T G 5 3 .
(CH2)2NEt2
96 .

3,9--4-

- 10 CPT
topo I, 4,8--4-
10 CPT96. 2,10--4

4-

CPT. 4-

topo

-215-

7:

P388 10 .
3,9-4- .
3,9--
topo I
89,97 .

ED-749

Merck-Banyu topo I .

H
N

R
N
O

OH

NHCH(CH2OH)2
N
O

HO

N
H

N
O

OH

OH

N
H

HO

HO
R'O

OH

R = F, R' = CH3 H
R = OH, R' = H

HO

ED-749
J-107088

OH

52. rebeccamycin - .

.
rebeccamycin,
, - -
.

topo I,

P38893. ED-749 ,
topo I, PKC
P388. , -
topo I ,

.
topo I
98 .

rebeccamycin DNA

-216-

8:

2-. REB-1 2-
DNA 99 ,
2-
topo I. HCHO
A-T 6-
,
G-C 2-
,
DNA 100 .
NH2
N
O

N
O

NH2

N
H

HO
HO

OH
REB-1

-
, - -,

DNA 101 . ,
DNA,
topo I
P388 P388/CPT5
CPT.

102 .

G1
L1210,

G1

. , REB-2
REB-3 DNA. ,

-217-

7:

REB-2 REB-4
DNA REB-2
.

O
N

H
N

O
N

NH
(H2C)4

HN

(CH2)3

HCl H2N

N
H

O
HCl

NH
CH2 HN
NH

NH2

N
H
(CH2)3

H2N

REB-2

(CH2)4

HCl H2N

NH
(H2C)4

N
H
(CH2)3

NH2 HCl

REB-3

NH2 HCl
REB-4

53. rebeccamycin
.

rebeccamycin.

DNA-topo

I-

rebeccamycin
DNA 103 .

, (REB-5) (REB-6).
DNA
rebeccamycin,
.
topo I,

HT29 549.

-218-

(CH2)2

N
HO

CH3O
HO

8:

N
H

(CH2)3

(CH2)2
N
H

N
NH

OH HN

REB-5

CH3O
HO

OH

HO

OH3C

N
N

HO

OH

NH

OH

OH HN

OH

HO

OH3C

REB-6

54. rebeccamycin.
. rebeccamycin
104 .
REB-(7-9) PKC,
REB-8 , topo I
in vitro
B16 P388,

DNA-topo

I.

4
105 . in vitro
, REB-10
L1210, REB-11
SK-N-MC NC-H69
, CDK1.
G1
.

topo I,
.


.

-219-

H
N

7:

H
N

Cl

H
N

Cl
OH

OCH3

HO

OH

OCH3

HO

REB-7
H
N

HO

OH

N
OH

H
N

O
NO2

REB-9

O2N

HO

OCH3

HO

REB-8

OH

N
OH

OCH3

OCH3

HO

REB-10

REB-11

55. rebeccamycin
.

Rebeccamycins.
[2,3-c] ,
rebeccamycin (REB-12) 106 .
topo I
.

OBu

BuO
O

O
BuO

HN

OBu

REB-12

-220-

8:

- -
rebeccamycin REB-(1319) 107, 108 , 109 , 110 .

rebeccamycin

topo I ,

topo I . ,

,

IC50
.

H
N

R
N

O
Br

OH

N
H

OH

HO

N
H

HO

OH

HO

HO

REB-14

H
N

N
H

OH

HO

OH

REB-13

23

HO

OH

REB-15 R = H
REB-16 R = CH3

H
N

NO2
N
O

N
H

N
OH

OH

HO

N
H

HO
HO

OH

N
O

N
H
OH

HO
OH

HO

REB-17

REB-18

HO

OH

REB-19

56. rebeccamycin.
.

[3]

-221-

rebeccamycin

7:

, .
, R-3
HL60

,
111 .

rebeccamycin

.

rebeccamycin
topo I DNA
112, 113 , 114 . DNA

topo

DNA

,
.
rebeccamycin.
BE-13793C Streptoverticillium sp.

C1

C11.

topo I
,

89.
BE-13793C in vivo
, ED-110 115 .
ED-110 topo I
BE-13793C,
,

-222-

8:

116 .
NB-506, BE13793C 117 109.
NB-506 topo I,
IC50 RNA polymerase II DNA polymerase
15 130
50% DNA topo I.
, IC50
3
staurosporine. NB-506 in vitro

.
topo I NB-506
,
,
topo I.

NB-506 , .

H
N

O
H
N

O
N
HO

HO

N
H

NHCHO
N
O

N
H

N
H
OH

HO

HO

OH

N
H

OH

HO

OH
HO

BE-13793C

N
OH

OH

HO

ED-110

OH
NB-506

57. rebeccamycin.

NB-506 in vivo

75%

118

( 26,
5076 Ehrlich)

-223-

7:

,
(MKN-45 , HCT-116, LS 180, PC-13)
.

, in vivo
M5076
in vitro .

LD50

taxol. ,
NB-506,

DNA topo I. topo I

NB-506 CPT,
topo I 119 . NB-506
topo I ,

DNA-topo

DNA,
. DNA, topo I NB-506
CPT, G+1 ,
1 (3 DNA
topo I)
( CPT), C 120 .
NB-506
-DNA GC 121 ,
DNA (triplex DNA),

122 .

topo I,
CPT
NB-506.

-224-

8:

NB-506 CPT
DNA-topo I 123 . NB-506
HL-60,
CPT,
,
pH, 3 8,
DNA 124 . NB-506
125 J107088.
J-107088
NB-506,

.

J-107088

NB-506 -6
2 10 1 11 NB-506 126 .

topo I NB-506 127 .

DNA-topo I

DNA.

, J-107088 DNA-
,

127.

DNA-

CPT
.
J107088 CPT.
CPT J-107088
, J-107088
topo I CPT.
J-107088
CPT J-107088
DNA. J107088 in vitro
CPT, Adriamycin, etoposide cisplatin.
,

-225-

7:

gp170. J-107088
,
NB-506.
2, 10 J-107088
topo I
123. ,
NB506 DNA topo I 128 .
2, 10
-6 NB-506 DNA
DNA C/T
G

G. o J-107088 DNA

C/T

G.

-6
topo I , DNA
.
J-107088 in vivo

129 .
DNA-
.
,

(therapeutic

window)

(human tumor xenografted

models) ,
LD10 75%
(tumor growth inhibitory dose, GID75).

-226-

8:

5. J-107088
Xenografts PC-3
.

(mg/m2, )

(LD10/GID75)

LD10*

GID75**

J-107088

578

15

38.5

NB-506

641

505

1.3

< 150

> 450

< 0.3

32

> 60

< 0.5

< 4.8

> 24

< 0.2

*LD10: 10%
**GID75: 75%

J-107088
NB-506, ,
,
. J-107088
in

vivo

P388/ADM

,
. J-107088

p- . ,

NB-506.

,
,

98.

in vitro topo I,
MKN-45
,
J-107088.
J-107088 in vivo

-227-

7:

(D-245

MG)

(D-54

(D-341

MG),

(D-456

MED),

MG),

procarbazine [D-245 MG-(PR)].

J-107088
. 7.6 62.1

D-456 MG 83% 130 . J-107088

cisplatin

antracycline taxane 131 .
[2,3-a]
,
Actinomadura melliaur: -24331, -24332, -24331
-24332 132, 133 , 134 . 24331,
2,4--4--L-.
rebeccamycin ,
DNA GC,
DNA 135 .
N
N

N
Cl
O
O

N
H

N
O

OH

OH
OCH3

RHN

O
O

N
H
OH

OH
OCH3

N
H

Cl

HO

OH
OCH3

OH

Cl

CH3HN
HO

HO

AT2433-A1, R = CH3
AT2433-A2, R = H

AT2433-B1, R = CH3
AT2433-B2, R = H

NSC-655649
(BMS181176)

58. [2,3-a]
.

-228-

8:

NSC 655649 -

rebeccamycin

. NSC 655649
, topo ,
topo II 136 .
epipodophyllotoxins

etoposide,

DNA
,
137 .
DNA .
- NSC 655649
poly(dd)
DNA doxorubicin
ethidium bromide 138 . Cl, rebeccamycin,
topo I,
in vivo 85,93.
NSC 655649 P388,
B16, 5076,
108, HCT116
54985, 139 , 140 .

,
136.

.


141,142 .
,

,

141.

-229-

7:

NSC 655649
, 143 .
topo I
Tjipanazoles
To 1991,
Tolypothrix tjipanasensis
, [2,3-a],
tjipanazoles desamido
rebeccamycin 144 .

Cl

Cl

Cl
N

N
H
OH

Tjipanazole A2

N
H
OH

Tjipanazole C3

OH

Tjipanazole C4

Cl

Cl
N

N
O

OH

HOH2C

OH
Tjipanazole B

OH

N
H
OH

N
O

OH

OH
OH
Tjipanazole G2

Cl

N
H
OH

N
O

OH

OH

Cl

Tjipanazole F1

Cl

Tjipanazole J

N
H

Tjipanazole D

59. tjipanazoles.

-230-

OH

Tjipanazole F2

Cl

Cl
N
H

N
H
OH

OH

Cl

N
H
OH

OH

Cl

Tjipanazole E

H
N

Tjipanazole G1

OH

N
H

OH

Tjipanazole C2

N
H
OH

Cl

N
H
OH

HO

N
H
OH
OH

OH

OH

OH

N
O

Tjipanazole C1

N
H
OH

OH

Cl

N
H
OH

Cl

Cl

Cl

OH

OH

Tjipanazole A1

N
O

OH

OH

N
H
OH

OH

Cl

Cl

N
H

N
H

Tjipanazole I

8:

tjipanazole

pyrrolo[3,4-c] . tjipanazoles D I

[2,3-a]. tjipanazoles A1, A2, C1C4, E F1, F2 Cl / (-D-glucosyl,

-6-deoxy-D-glucosyl, -L-rhamnosyl, -D-xylosyl)
.
tjipanazoles in vivo
Candida albicans. ,
tjipanazoles A1 A2
. , ,

,
145 .
tjipanazoles
pyrrolo[3,4-c] ,
rebeccamycin in vitro in vivo
. , tjipanazoles
PKC 10-6 .

tjipanazoles 146, 147 , 148 , 149 ,
,

150 , 151 , 152 , 153 , 154

staurosporine

148,

tjipanazoles - rebeccamycin
topo I, in vitro

Gram 155 .

-231-

N
O

OH

7:

N
H

N
O

HO
CH3O

OH

N
H

HO
OH

CH3O

OH

TJI-1
O2N
NO2
N
O

OH

N
H

N
O

HO
CH3O

OH

N
H

N
O

HO
OH

OH

N
H

HO

CH3O

TJI-2

OH

CH3O

TJI-3

OH
TJI-4

60. tjipanazoles.

in vitro
. TJI-1
TJI-4 , TJI-2
.
TJI-3
rebeccamycin, .

L1210 G2 0.25 ,
rebeccamycin

. ,
PKCz, CDK1, CDK5/p25 ERK1,

topo I TJI-3
TJI-2.
DNA,
DNA
tjipanazoles CPT
rebeccamycin dechlororebeccamycin.

-232-

8:

L1210
, TJI-3,
topo I.
rebeccamycin
topo I,
.
Candida albicans, TJI-1, 2, 4
Gram
(B. Cereus S. Chartreuses), TJI-1
Gram E. Coli.

Arcyriaflavins
arcyriaflavins A, B C
Arcyria nutants Arcyria denutata 156 , arcyriaflavins C
, Metatrichia vesparium 157 .
[2,3-a]
2 10

arcyriaflavin

D,

Dictydiaethalium plumbeum
2 9.
H
N

N
H

N
H

N
H

Arcyriaflavin A

H
N

H
N

OH

N
H

Arcyriaflavin B

H
N

HO
HO

N
H

N
H

OH

Arcyriaflavin C

N
H

N
H

OH

Arcyriaflavin D

61. Arcyriaflavins.
arcyriaflavins .

-233-

arcyriaflavin

A.

7:

topo I (10
rebeccamycin, MIC=10 g/mL),
topo II (MIC>10g/mL)85. PKC (IC50=44.7 )
PKA (IC50=60 )85, 158 , 159 , /CDKs
(CDK4/D1 IC50=0.16 , CDK2/E IC50=0.53 , CDK1/B IC50=1.1
) 160 . in vitro
P388 (IC50=4 )85
Bacillus cereus (MIC= >50 )85. , arcyriaflavin A

(human cytomegalovirus, HCMV)
IC50=0.2 161 .
HCMV , ,
.

(AIDS)
162,163 .
HCMV , ganciclovir (GCV),
foscarnet (PFA) cidofovir (HPMPC) DNA
.

),

(,

, .
arcyriaflavin A pUL97
HCMV161,

164 . pUL97, GCV

DNA

,
. pUL97
GCV. , arcyriaflavin A,
161,165 ,
166 .

-234-

8:

5,11-Dihydroindolo[3,2-b]carbazoles
2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD-1 (TCDD
receptor aryl hydrocarbon (Ah) receptor),

167 . ,

,
,

P450A1

(CYP1A1),

TCDD 168 . TCDD

, [2,3-a]
TCDD-2.

Cl

Cl

Cl

Cl

TCDD-1

H
N

N
H

H
N

N
H

N
H
TCDD-2

TCDD-3

H
N

TCDD-4

62. TCDD.
TCDD-2, in vivo
169 ,
TCDD. , TCDD3 170 (Kd=710-11) 171 ,
TCDD-1 5-8 172 . ,
TCDD-4,
.

6-170

5,11-[3,2-b]

6,12- 173

TCDD.
TCDD-2,
TCDD-5 , TCDD-6 TCDD-7 174 .

-235-

7:

TCDD-2 (TCDD-8,
9, 10, 11)
TCDD-12 TCDD-13 TCDD.
HO

Br

CH3O
H
N
N
H

N
H

N
H
OH

TCDD-5

OCH3

TCDD-6

Br

TCDD-7

H
N

N
N

H
N

H
N

N
N

TCDD-9

TCDD-8

TCDD-10

OH
N

N
H

N
HO

TCDD-12

TCDD-11

N
H

63.

TCDD-13

5,11-[3,2-b],

TCDD.
, TCDD-14 TCDD-15
175 in vivo TCDD-2.
TCDD-14
TCDD 176 ,

mRNA CYP1A1
TCDD175.
O

N
H

H
N
N
H

O
TCDD-14

O
TCDD-15

-236-

N
H

8:

5,6,11,12-[2,3-a]

5,6,11,12- [2,3-a]
,

177 .

, -1
Cl E.
Coli, P. Aeruginosa B. Subtilis,
C. albicans, T. rubrum, A. niger.,
Mycobacterium tuberculosis.
Cl
N
H

N
H

TETIN-1

topo I

Hoechst 33342 33258

DNA, .
Hoechst 33342
DNA 178 . ,

topo I178. 2-(4)-1H-
topo I , DNA
Hoechst,
CPT,
DNA 179 .

-237-

7:

OCH2CH3
H N

H
N

H
N

NH

OCH3

N
H

N
H
Hoechst 33342

2,5-

R = CHO
COOH
CONH2 CH2NH2
NO2
CN

64. topo I.

DNA
Bulgarein
bulgarein
10 ,

DNA,

,
,
netropsin 180 .
DNA
DNA
DNA, morpholinyldoxorubicin, actinomycin D aclarubicin
(aclacinomycin

A)

topo

I 181, 182 , 183 .

aclarubicin

CPT

topo I.
-

topo I
topo II. NU/ICFR 505,
topo I
DNA 184 .

DNA 185 .

-238-

8:

MeVa
MeVa
Sar
Sar
Pro
Pro
D Val
D Val
Thr
Thr
CHOH
CO
NH2
N

OH

HO

CH2 O
O HN C C
CH3
H O CH
2

OH
HO

O
Bulgarein

OH

NU/ICRF 505

Actinomycin D

65. topo
I DNA.

topo I
, DNA,
DNA doxorubicin,
aclacinomycin

A,

naphtacenecarboxamide,

distamycin,

Hoechst

33342

DNA topo I.
DNA 186 .
DNA
/ DNA.
-Lapachone,
lapacho (Tabebuia avellanedae) . ,
topo I,
187-188 . ,
topo I , topo I 189

190

DNA

acetylshikonin, Lithospermi radix,

topo I 191 .
topo I

.
, DNA,
corilagin chebulagic acid,

-239-

7:

Erodium stephnianum 192,193 . , velutin,

Lethedon tanaensis , topo I
. ,
epi-oligothiadiketopiperazine, TAN-1496 A,
C , Microsphaeropsis sp.
topo I 194 . , elagic acid flavellagic acid
topo I .

,
DNA, topo I.

OH O

OCH3
OH
O

CH3O
O

OH O

Menadione
(Vit. K3)

-Lapachone

OHHO

OH

HO

OH
O

O
O
O

R=H

OH
OH
OH

O
R

R=

HOOC

O
O

O
Chebulagic
Acid:

Velutin

Acetylshikonin

HO

Corilagin:

OH O

C O

O C

H2
C

CH

H
OH

HO
O

OH

66. topo I

topo

,
topo II,
.

-240-

8:

Nitiss J., Wang J.C., DNA topoisomerase-targeting antitumor drugs

can be studied in yeast, Proc. Natl. Acad. Sci. USA, 7501-7505, 85,
1988.

Wall M.E., Camptothecin and Taxol, In:

Chronicles of Drug Discovery, American
Washington D. C., p. 327, 3, 1993.

Wall M.E., Wani M.C., Cook C.E., Palmer K.H., McPhail A.T., Sim G.
A., Plant antitumor agents. I. Isolation and structure of camtothecin,
a novel alkaloidal leukemia and tumor inhibitor from Camptotheca
acuminata, J. Am. Chem. Soc., 3888-3890, 88, 1966.

Gottlieb J.A., Luce J.K., Treatment of malignant melanoma with

camptothecin (NSC-100880), Cancer Chemother. Rep. 1, 103-105,
56, 1972.

Wani M.C., Nicholas A.W., Wall M.E., Plant antitumor agents. 28.
Resolution of a key tricyclic synthon, 5'(RS)-1,5-dioxo-5'-ethyl-5'hydroxy-2'H,5'H,6'H-6'-oxopyrano[3',4'-f]delta
6,8-tetrahydroindolizine: Total synthesis and antitumor activity of 20(S)- and 20(R)camptothecin, J. Med. Chem., 2317-2319, 30, 1987.

Kingsbury W.D., Boehm J.C., Jakas D.R., Holden K.G., Hecht S.M.,
Gallagher G., Caranfa M.J., McCabe F.L., Faucette L.F., Johnson R.K.,
Synthesis of water-soluble (aminoalkyl)camptothecin analogues:
Inhibition of topoisomerase I and antitumor activity, J. Med. Chem.,
98-107, 34, 1991.

Fassberg J., Stella V.J., A kinetic and mechanistic study of the

hydrolysis of camptothecin and some analogues, J. Pharm. Sci., 676684, 81, 1992.

Hertzberg R.P., Caranfa M.J., Holden K.G., Jakas D.R., Gallagher G.,
Mattern M.R., Mong S.M., Bartus J.O., Johnson R.K., Kingsbury W.D.,
Modification of the hydroxy lactone ring of camptothecin: inhibition
of mammalian topoisomerase I and biological activity, J. Med.
Chem., 715-720, 32, 1989.

Gallo R.C., Whang-Peng J., Adamson R.H., Studies on the antitumor

activity, mechanism of action, and cell cycle effects of camptothecin,
J. Natl. Cancer Inst., 789-795, 46, 1971.

10

Hsiang Y.H., Hertzberg R., Hecht S., Liu L.F., Camptothecin induces
protein-linked DNA breaks via mammalian DNA topoisomerase I, J.
Biol. Chem., 14873-14878, 260, 1985.

11

Hsiang Y.H., Lihou M.G., Liu L.F., Arrest of replication forks by drugstabilized topoisomerase I-DNA cleavable complexes as a mechanism
of cell killing by camptothecin, Cancer Res., 5077-5082, 49, 1989.

12

Pommier Y., Pourquier P., Urasaki Y., Wu J., Laco G.S.,

Topoisomerase I inhibitors: Selectivity and cellular resistance, Drug
Resist. Updates, 307-318, 2, 1999.

13

Hertzberg R.P., Caranfa M.J., Hecht S.M., On the mechanism of

topoisomerase I inhibition by camptothecin: Evidence for binding to
an enzyme-DNA complex, Biochemistry, 4629-4638, 28, 1989.

-241-

Lednicer D. (Ed.),
Chemical Society,

7:

14

Pommier Y., Tanizawa A., Kohn K.W., Mechanisms of topoisomerase

I inhibition by anticancer drugs, Adv. Pharmacol., 73-92, 29B, 1994.

15

Arimondo P.B., Boutorine A., Baldeyrou B., Bailly C., Kuwahara

M.,Hecht S.M., Sun J.-S., Garestier T.,Helene C., Design and
optimization of camptothecin conjugates of triple helix-forming
oligonucleotides
for
sequence-specific
DNA
cleavage
by
topoisomerase I, J. Biol. Chem., 3132-3140, 277, 2002.

16

Redinbo M.R., Stewart L., Kuhn P., Champoux J.J., Hol W.G., Crystal
structures of human topoisomerase I in covalent and noncovalent
complexes with DNA, Science, 1504-1513, 279, 1998.

17

Pommier Y., Kohlhagen G., Kohn K.W., Leteurtre F., Wani M.C., Wall
M.E., Interaction of an alkylating camptothecin derivative with a DNA
base at topoisomerase I-DNA cleavage sites, Proc. Natl. Acad. Sci.
USA, 8861-8865, 92, 1995.

18

Kerrigan J.E., Pilch D.S., A structural model for the ternary cleavable
complex formed between human topoisomerase I, DNA, and
camptothecin, Biochemistry, 9792-9298, 40, 2001.

19

Laco G.S., Collins J.R., Luke B.T., Kroth H., Sayer J.M., Jerina D.M.,
Pommier Y., Human topoisomerase I inhibition: docking
camptothecin and derivatives into a structure-based active site
model, Biochemistry, 1428-1235, 41, 2002.

20

Fujimori A., Harker W.G., Kohlhagen G., Hoki Y., Pommier Y.,
Mutation at the catalytic site of topoisomerase I in CEM/C2, a human
leukemia cell line resistant to camptothecin, Cancer Res., 13391346, 55, 1995.

21

Jensen A.D., Svejstrup J.Q., Purification and characterization of

human topoisomerase I mutants, Eur. J. Biochem., 389-394, 236,
1996.

22

Urasaki Y., Laco G.S., Pourquier P., Takebayashi

Gioffre C., Zhang H., Chatterjee D., Pantazis
Characterization of a novel topoisomerase I
camptothecin-resistant human prostate cancer cell
1964-1969, 61, 2001.

23

Lima C.D., Wang J.C., Mondragon A., Three-dimensional structure of

the 67K N-terminal fragment of E. coli DNA topoisomerase I, Nature,
138-146, 367, 1994.

24

Pommier Y., Leteurtre F., Fesen M.R., Fujimori A., Bertrand R., Solary
E., Kohlhagen G., Kohn K.W., Cellular determinants of sensitivity
and resistance to DNA topoisomerase inhibitors, Cancer Invest.,
530-542, 12, 1994.

25

Desai S.D., Liu L.F., Vazquez-Abad D., D'Arpa P., Ubiquitindependent destruction of topoisomerase I is stimulated by the
antitumor drug camptothecin, J. Biol. Chem., 24159-24164, 272,
1997.

26

Rallabhandi P., Hashimoto K., Mo Y.-Y., Beck W.T., Moitra P.K.,

D'Arpa P., Sumoylation of topoisomerase I is involved in its
partitioning between nucleoli and nucleoplasm and its clearing from

-242-

Y., Kohlhagen G.,

P., Pommier Y.,
mutation from a
line, Cancer Res.,

8:

nucleoli in response to camptothecin, J. Biol. Chem., 40020-40026,

277, 2002.
27

Rossi F., Labourier E., Gallouzi I.E., Derancourt J., Allemand E., Divita
G., Tazi J., The C-terminal domain but not the tyrosine 723 of
human DNA topoisomerase I active site contributes to kinase
activity, Nucleic Acids Res., 2963-2970, 26, 1998.

28

Walowsky C., Fitzhugh D.J., Castano I.B., Ju J.Y., Levin N.A.,

Christman M.F., The topoisomerase-related function gene TRF4
affects cellular sensitivity to the antitumor agent camptothecin, J.
Biol. Chem., 7302-7308, 274, 1999.

29

Kawato Y., Sekiguchi M., Akahane K., Tsutomi Y., Hirota Y., Kuga H.,
Suzuki W., Hakusui H., Sato K., Inhibitory activity of camptothecin
derivatives against acetylcholinesterase in dogs and their binding
activity to acetylcholine receptors in rats, J. Pharm. Pharmacol.,
444-448, 45, 1993.

30

Wall M.E., Wani M.C., Nicholas A.W., Manikumar G., Tele C. Moore L.,
Truesdale A., Leitner P., Besterman J.M., Plant antitumor agents. 30.
Synthesis and structure activity of novel camptothecin analogs, J.
Med. Chem., 2689-2700, 36, 1993.

31

Lackey K., Besterman J.M., Fletcher W., Leitner P., Morton B.,
Sternbach D.D., Rigid analogs of camptothecin as DNA
topoisomerase I inhibitors, J. Med. Chem., 906-911, 38, 1995.

32

Potmesil M., Pinedo H (Eds), Camptothecins: New Anticancer Agents,

CRC Press, Boca Raton, 1995.

33

Kawato Y., Terasawa H., Recent advances in the medicinal chemistry

and pharmacology of camptothecin, In: Ellis G.P., Luncombe D.K.
(Eds), Progress in Medicinal Chemistry, Elsevier, London pp. 70-109,
34, 1997.

34

Yaegashi T., Sawada S., Nagata H., Furuta T., Yokokura T., Miyasaka
T., Synthesis and antitumor activity of 20(S)-camptothecin
derivatives. A-ring-substituted 7-ethylcamptothecins and their E-ringmodified water-soluble derivatives, Chem. Pharm. Bull., 2518-2525,
42, 1994.

35

Kaneda N., Nagata H., Furuta T., Yokokura T., Metabolism and
pharmacokinetics of the camptothecin analogue CPT-11 in the
mouse, Cancer Res., 171-1720, 50, 1990.

36

Emerson D.L., Besterman J.M., Brown H.R., Evans M.G., Leitner P.P.,
Luzzio M.J., Shaffer J.E., Sternbach D.D, Uehling D., Vuong A., In
vivo antitumor activity of two new seven-substituted water-soluble
camptothecin analogues, Cancer Res., 603-609, 55, 1995.

37

Van Hattum A.H., Schluper H.M.M., Hausheer F.H., Pinedo H.M.,

Boven E., Novel camptothecin derivative BNP1350 in experimental
human ovarian cancer: Determination of efficacy and possible
mechanisms of resistance, Int. J. Cancer, 22-29, 100, 2002.

38

Dallavalle S., Ferrari A., Biasotti B., Merlini L., Penco S., Gallo G.,
Marzi M., Tinti M.O., Martinelli R., Pisano C., Carminati P., Carenini
N., Beretta G., Perego P., De Cesare M., Pratesi G., Zunino F., Novel

-243-

7:

7-oxyiminomethyl derivatives of camptothecin with potent in vitro

and in vivo antitumor activity, J. Med. Chem., 3264-3274, 44, 2001.
39

Ihara M., Noguchi K., Ohsawa T., Fukumoto K., Kametani T., Studies
on the syntheses of heterocyclic compounds and natural products.
999. Double enamine annelation of 3,4-dihydro-1-methyl--carboline
and
isoquinoline
derivatives
with
6-methyl-2-pyrone-3,5dicarboxylates and its application for the synthesis of ()camptothecin, J. Org. Chem., 3150-3156, 48, 1983.

40

Nicholas A. W., Wani M.C., Manikumar G., Wall M.E., Kohn K.W.,
Pommier Y., Plant antitumor agents. 29. Synthesis and biological
activity of ring D and ring E modified analogues of camptothecin, J.
Med. Chem., 972-978, 33, 1990.

41

Sawada S., Nokata K., Furuta T., Yokokura T., Miyasaka T.,
Chemical modification of an antitumor alkaloid camptothecin:
synthesis and antitumor activity of 7-C-substituted camptothecins,
Chem. Pharm. Bull., 2574-2580, 39, 1991.

42

Wang H.-K., Liu S.-Y., Hwang K.-M., McPhail A.T., Lee K.-H.,
Antitumor agents. 160. The synthesis of 5-substituted camptothecins
as potential inhibitors of DNA topoisomerase I, Bioorg. Med. Chem.
Lett., 77-82, 5, 1995.

43

Subrahmanyam D., Venkateswarlu A., Venkateswara R.K.,Sastry

T.V., Vandana G., Kumar S.A., Novel C-ring analogues of 20(S)camptothecin-part-2: Synthesis and in vitro cytotoxicity of 5-Csubstituted 20(S)-camptothecin analogues, Bioorg. Med. Chem.
Lett., 1633-1638, 9, 1999.

44

Sugimori M., Ejima A., Ohsuki S., Matsumoto K., Kawato Y., Yasuoka
M., Tagawa H., Terasawa H., Antitumor agents. VI. Synthesis and
antitumor activity of ring A-, ring B-, and ring C-modified derivatives
of camptothecin, Heterocycles, 81-94, 38, 1994.

45

Lavergne O., Lesueur-Ginot L., Rodas F.P., Bigg D.C.H., BN 80245:

an E-ring modified camptothecin with potent antiproliferative and
topoisomerase I inhibitory activities, Bioorg. Med. Chem. Lett.,
2235-2238, 7, 1997.

46

Larsen A.K., Gilbert C., Chyzak G., Plisov S.Y., Naguibneva I.,
Lavergne O., Lesueur-Ginot L., Bigg D.C., Unusual potency of BN
80915, a novel fluorinated E-ring modified camptothecin, toward
human colon carcinoma cells, Cancer Res., 2961-2967, 61, 2001.

47

Du W., Curran D.P., Bevins R. L, Zimmer S.G., Zhang J., Burke T.G.,
Synthesis and evaluation of a novel E-ring modified alpha-hydroxy
keto ether analogue of camptothecin, Bioorg. Med. Chem. Lett., 103110, 10, 2002.

48

Cagir A., Jones S.H., Gao R., Eisenhauer B.M., Hecht S.M., Luotonin
A. A naturally occurring human DNA topoisomerase I poison, J. Am.
Chem. Soc., 13628-13629, 125, 2003.

49

Hautefaye P., Cimetiere B., Pierre A., Leonce S., Hickman J., Laine
W., Bailly C., Lavielle G., Synthesis and pharmacological evaluation
of novel non-lactone analogues of camptothecin, Bioorg. Med. Chem.
Lett., 2731-2735, 13, 2003.

-244-

8:

50

Houghton P.J., Cheshire P.J., Myers L., Stewart C.F., Synold T.W.,
Houghton
J.A.,
Evaluation
of
9-dimethylaminomethyl-10hydroxycamptothecin against xenografts derived from adult and
childhood solid tumors, Cancer Chemother. Pharmacol., 229-239,
31, 1992.

51

Friedman H.S., Houghton P.J., Schold S.C., Keir S., Bigner D.D.,
Activity of 9-dimethylaminomethyl-10-hydroxycamptothecin against
pediatric and adult central nervous system tumor xenografts, Cancer
Chemother. Pharmacol., 171-174, 34, 1994.

52

Pratesi G., Tortoreto M., Corti C., Giardini R., Zunino F., Successful
local regional therapy with topotecan of intraperitoneally growing
human ovarian carcinoma xenografts, Br. J. Cancer., 525-528, 71,
1995.

53

Creemers G.J., Wanders J., Gamucci T., et al., Topotecan in

colorectal cancer: A phase II study of the EORTC early clinical trials
group, Ann. Oncol., 844-846, 6, 1995.

54

Pizzolato J.F, Saltz L.B., The camptothecins, Lancet, 2235-2242,

361, 2003.

55

Giovanella B.C., Stehlin J.S., Wall M.E., Wani M.C., Nicholas A.W., Liu
L.F., Silber R., Potmesil M., DNA topoisomerase I-targeted
chemotherapy of human colon cancer in xenografts, Science, 10461048, 246, 1989.

56

Pitot H.C., Knost J.A., Mahoney M.R., et al., A North Central Cancer
Treatment Group Phase II trial of 9-aminocamptothecin in previously
untreated patients with measurable metastatic colorectal carcinoma,
Cancer, 1699-1705, 89, 2000.

57

Vokes E.E., Gordon G.S., Rudin C.M., et al., A phase II trial of 9aminocaptothecin (9-AC) as a 120h infusion in patients with nonsmall cell lung cancer, Invest. New Drugs, 329-333, 19, 2001.

58

Verschraegen C.F., Gupta E., Loyer E., et al., A phase II clinical and
pharmacological study of oral 9-nitrocamptothecin in patients
withrefractory epithelial ovarian, tubal or peritoneal cancer,
Anticancer Drugs, 375-383, 10, 1999.

59

Raymond E., Campone M., Stupp R., et al., Multicentre phase II and
pharmacokinetic
study
of
RFS2000
(9-nitro-camptothecin)
administered orally 5 days a week in patients with glioblastoma
multiforme, Eur. J. Cancer, 1348-1350, 38, 2002.

60

Ellerhorst J.A., Bedikian A.Y., Smith T.M., Papadopoulos N.E., Plager

C., Eton O., Phase II trial of 9-nitrocamptothecin (RFS 2000) for
patientswith metastatic cutaneous or uveal melanoma, Anticancer
Drugs, 169-172, 13, 2002

61

Stehlin J.S., Giovanella B.C., Natelson E.A., et al., A study of 9nitrocamptothecin (RFS-2000) in patients with advanced pancreatic
cancer, Int. J. Oncol., 821-831, 14, 1999.

62

Sharma S., Kemeny N., Schwartz G.K., et al., Phase I study of

topoisomerase I inhibitor exatecan mesylate (DX-8951f) given as
weekly 24-hour infusions three of every four weeks, Clin. Cancer
Res., 3963-3970, 7, 2001.

-245-

7:

63

Royce M., Saltz L.B., Rowinsky E.K., et al., A phase II study of

intravenous exatecan mesylate (Dx-8951f, Dx) administered daily for
five days every three weeks to patients with advanced or metastatic
adenocarcinoma of the colon or rectum, Abstract 1129, Proc. Am.
Soc. Clinical Oncol., 2000.

64

OReilly E, Hammond L.A., Sharma S., et al., A phase II study of

exatecan mesylate (DX-8951F, DX) in advanced pancreatic cancer,
Abstract 1170, Proc. Am. Soc. Clinical Oncol., 2000.

65

Abou-Alfa G.K., OReilly E.M., Rowinsky E.K., et al., Final results of a

phase II study of DX-8951f (DX, exatecan mesylate) in biliary tree
cancers, Abstract 561, Proc. Am. Soc. Clinical Oncol., 2002.

66

Yamashita Y., Kawada S., Fujii N., Nakano H., Induction of

mammalian DNA topoisomerase I and II mediated DNA cleavage by
saintopin, a new antitumor agent from fungus, Biochemistry, 58385845, 30, 1991.

67

Fujii N., Yamashita Y., Mizukami T., Nakano H., Correlation between
the formation of cleavable complex with topoisomerase I and growthinhibitory activity for saintopin-type antibiotics, Mol. Pharmacol.,
269-276, 51, 1997.

68

Leteurtre F., Fujimori A., Tanizawa A., Chhabra A., Mazumder A.,
Kohlhagen G., Nakano H., Pommier Y., Saintopin, a dual inhibitor of
DNA topoisomerases I and II, as a probe for drug-enzyme
interactions, J. Biol. Chem., 28702-28707, 269, 1994.

69

Fang S. D. Wang L.K., Hecht S.M., Inhibitors of DNA topoisomerase I

isolated from the roots of Zanthoxylum nitidum, J. Org. Chem.,
5025-5027, 58, 1993.

70

Wang L.K., Johnson R.K., Hecht S.M., Inhibition of topoisomerase I

function by nitidine and fagaronine, Chem. Res. Toxicol., 813-818,
6, 1993.

71

Larsen A.K., Grondard L., Couprie J., Desoiz B., Comof L., Jardillier
J.-C., Riou J.-F., The antileukemic alkaloid fagaronine is an inhibitor
of DNA topoisomerases I and II, Biochem. Pharmacol., 1403-1412,
19, 1993.

72

Janin Y.L., Croisy A., Riou J.F., Bisagni E., Synthesis and evaluation
of new 6-amino-substituted benzo[c]phenanthridine derivatives, J.
Med. Chem., 3686, 36, 1993.

73

Zee-Cheng K.Y., Paull K.D., Cheng C.C., Experimental antileukemic

agents. Coralyne, analogs, and related compounds, J. Med. Chem.,
347-351, 17, 1974.

74

Shan X., Jones D.P., Hashmi M., Anders M.W., Selective depletion of
mitochondrial glutathione concentrations by (R,S)-3-hydroxy-4pentenoate potentiates oxidative cell death, Chem. Res. Toxicol., 7581, 6, 1993.

75

Gatto B., Sanders M.M., Yu C., Wu H.Y., Makhey D., LaVoie E.J., Liu
L.F., Identification of topoisomerase I as the cytotoxic target of the
protoberberine alkaloid coralyne, Cancer Res., 2795-2800, 565,
1996.

-246-

8:

76

Kobayashi Y., Yamashita Y., Fujii N., Takaboshi K., Kawakami T.,
Kawamura M., Mizukami T., Nakano H., Inhibitors of DNA
topoisomerase I and II isolated from the Coptis rhizomes, Planta
Med., 414-418, 61, 1995.

77

Abigerges D., Armand J.P., Chabot G.G., Bruno R., Bissery M.C.,
Bayssas M., Klink-Alakl M., Clavel M., Catimel G., Phase I and
pharmacology study of intoplicine (RP 60475; NSC 645008), novel
topoisomerase I and II inhibitor, in cancer patients, Anticancer
Drugs, 166-174, 7, 1996.

78

Riou J.F., Helissey P., Grondard L., Giorgi-Renault S., Inhibition of

eukaryotic
DNA
topoisomerase
I
and
II
activities
by
indoloquinolinedione derivatives, Mol. Pharmacol., 699-706, 40,
1991.

79

Kokoshka J.M., Capson T.L., Holden J.A., Ireland C.M., Barrows L.R.,
Differences in the topoisomerase I cleavage complexes formed by
camptothecin and wakayin, a DNA-intercalating marine natural
product, Anticancer Drugs, 758-765, 7, 1996.

80

Kohlhagen G., Paull K., Cushman M., Nagafufuji P., Pommier Y.,
Protein-linked DNA strand breaks induced by NSC 314622, a novel
noncamptothecin topoisomerase I poison, Mol. Pharmacol., 50-58,
54, 1998.

81

Fujimori A., Hoki Y., Popescu N.C., Pommier Y., Silencing and
selective methylation of the normal topoisomerase I gene in
camptothecin-resistant CEM/C2 human leukemia cells, Oncol. Res.,
295-301, 8, 1996.

82

Nettleton D.E., Doyle T.W., Krishnan B., Matsumoto G.K., Clardy J.,
Isolation and structure of rebeccamycin - a new antitumor antibiotic
from Nocardia aerocoligenes, Tet. Lett , 4011-4014, 26, 1985.

83

Kaneko T., Wong H., Okamoto K.T., Clardy J., Two synthetic
approaches to rebeccamycin, Tet. Lett , 4015-4018, 26, 1985.

84

Prudhomme M., Indolocarbazoles as anti-cancer agents, Curr.

Pharm. Des., 265-290, 3, 1997.

85

Rodrigues Pereira E., Belin L., Sancelme M., Prudhomme M., Ollier
M., Rapp M., Severe D., Riou J.-F., Fabbro D., Meyer T., Structureactivity relationships in a series of substituted indolocarbazoles:
Topoisomerase I and protein kinase c inhibition and antitumoral and
antimicrobial properties, J. Med. Chem., 4471-4477, 39, 1996.

86

Bush J.A., Long B.H., Catino J.J., Bradner W.T., Tomita K.,
Production and biological activity of rebeccamycin, a novel antitumor
agent, J. Antibiot., 668-78, 40, 1987.

87

Lam K.S., Mattei J., Forenza S., Carbon catabolite regulation of

rebeccamycin production in Saccharothrix aerocolonigenes, J. Ind.
Microbiol., 105-108, 4, 1989.

88

Matson J.A., 4'-Deschlororebeccamycin pharmaceutical composition,

US Pat. 4524145/1985, Chem. Abstr., 159104d, 103, 1985.

89

Kojiri K., Kondo H., Yoshinari T., Arakawa H., Nakajima S., Satoh F.,
Kawamura K., Okura A., Suda H., Okanishi M., A new antitumor

-247-

7:

substance BE-13793C, produced by a streptomycete. Taxonomy,

fermentation, isolation, structure determination and biological
activity, J. Antibiot., 723-728, 44, 1991.
90

Kaneko T., Wong H., Utzig J., Schurig J., Doyle T., "Water soluble
derivatives of rebeccamycin, J. Antibiot., 125-127, 43, 1990.

91

Gallant M., Link J.T., Danishefsky S.J., A stereoselective synthesis of

indole--N-glycosides:
An
application
to
the
synthesis
of
rebeccamycin, J. Org. Chem., 343-349, 58, 1993.

92

Faul M.M., Winneroski L.L., Krumrich C.A., Synthesis of

Rebeccamycin and 11-Dechlororebeccamycin, J. Org. Chem., 24652470, 64, 1999.

93

Anizon F., Belin L., Moreau P., Sancelme M., Voldoire A., Prudhomme
M., Ollier M., Severe D., Riou J.-F., Bailly C., Fabbro D., Meyer T.,
Syntheses and biological activities (topoisomerase inhibition and
antitumor and antimicrobial properties) of rebeccamycin analogues
bearing modified sugar moieties and substituted on the imide
nitrogen with a methyl group, J. Med. Chem., 3456-3465, 40, 1997.

94

Prudhomme M., Recent developments of rebeccamycin analogues as

topoisomerase I inhibitors and antitumor agents, Curr. Med. Chem.,
1189-1212, 7, 2000.

95

Bailly C., Riou J.-F., Colson P., Houssier C., Rodrigues Pereira E.,
Prudhomme M., DNA cleavage by topoisomerase I in the presence of
indolocarbazole derivatives of rebeccamycin, Biochemistry, 39173929, 36, 1997.

96

Long B.H., Rose W.C., Vyas D.M., Matson J.A., Forenza S., Discovery
of antitumor indolocarbazoles: Rebeccamycin, NSC 655649, and
fluoroindolocarbazoles., Curr. Med. Chem. Anti Cancer Agents, 255266, 2, 2002.

97

Zembower D.E., Zhang H.,. Lineswala J.P, Kuffel M.J., Aytes S.A.,
Ames M.M., Indolocarbazole poisons of human topoisomerase I:
Regioisomeric analogues of ED-110, Bioorg. Med Chem. Lett., 145150, 9, 1999.

98

Ohkubo M., Nishimura T., Kawamoto H., Nakano M., Honma T.,
Yoshinari T., Arakawa H., Suda H., Morishima H., Nishimura S.,
Synthesis and biological activities of NB-506 analogues modified at
the glucose group, Bioorg. Med Chem. Lett., 419-422, 10, 2000.

99

Bailly C., Qu X., Anizon F., Prudhomme M., Riou J.-F., Chaires J.B.,
Enhanced binding to DNA and topoisomerase I inhibition by an
analog of the antitumor antibiotic rebeccamycin containing an amino
sugar residue, Mol. Pharmacol., 377-385, 55, 1999.

100

Bailly C., Goossens J.-F., Laine W., Anizon F., Prudhomme M., Ren J.,
Chaires J.B., Formaldehyde-induced alkylation of a 2'-aminoglucose
rebeccamycin derivative to both A.T and G.C base pairs in DNA, J.
Med. Chem., 4711-4720, 43, 2000.

101

Moreau P., Anizon F., Sancelme M., Prudhomme M., Bailly C., Severe
D., Riou J.-F., Fabbro D., Meyer T., Aubertin A.-M., Syntheses and
biological activities of rebeccamycin analogues. Introduction of a
halogenoacetyl substituent, J. Med. Chem., 584-592, 42, 1999.

-248-

8:

102

Moreau P., Sancelme M., Bailly C., Leonce S., Pierre A., Hickman J.,
Pfeiffer B., Prudhomme M., Synthesis and biological activities of
indolocarbazoles bearing amino acid residues, Eur. J. Med. Chem.,
887-897, 36, 2001.

103

Marminon C., Facompre M., Bailly C., Hickman J., Pierre A. , Pfeiffer
B., Renard P., Prudhomme M., Dimers from dechlorinated
rebeccamycin: Synthesis, interaction with DNA, and antiproliferative
activities, Eur. J. Med. Chem., 435-440, 37, 2002.

104

Anizon F., Moreau P., Sancelme M., Voldoire A., Prudhomme M.,
Ollier M., Severe D., Riou J.-F., Bailly C., Fabbro D., Meyer T.,
Aubertin A.-M., Syntheses, biochemical and biological evaluation of
staurosporine
analogues
from
the
microbial
metabolite
rebeccamycin, Bioorg. Med Chem., 1597-1604, 6, 1998.

105

Marminon C., Anizon F., Moreau P., Leonce S., Pierre A., Pfeiffer B.,
Renard P., Prudhomme M., Syntheses and antiproliferative activities
of new rebeccamycin derivatives with the sugar unit linked to both
indole nitrogens, J. Med. Chem., 1330-1339, 45, 2002.

106

Voldoire A., Sancelme M., Prudhomme M., Colson P., Houssier C.,
Bailly C., Leonce S., Lambel S., Rebeccamycin analogues from
indolo[2,3-c]carbazole, Bioorg. Med. Chem., 357-365, 9, 2001.

107

Marminon C., Pierre A., Pfeiffer B., Perez V., Leonce S., Renard P.,
Prudhomme M., Syntheses and antiproliferative activities of
rebeccamycin analogues bearing two 7-azaindole moieties, Bioorg.
Med. Chem., 679-687, 11, 2003.

108

Marminon C., Pierre A., Pfeiffer B., Perez V., Leonce S., Joubert A.,
Bailly C., Renard P., Hickman J., Prudhomme M., Syntheses and
antiproliferative activities of 7-azarebeccamycin analogues bearing
one 7-azaindole moiety, J. Med. Chem., 609-622, 46, 2003.

109

Ohkubo M., Kawamoto H., Ohno T., Nakano M., Morishima H.,
Synthesis of NB-506, a new anticancer agent, Tet., 585-592, 53,
1997.

110

Routier S., Coudert G., Merour J.-Y., Caignard D.H., First synthesis
of symmetrical and non-symmetrical azaindolocarbazole derivatives,
Tet. Lett., 2561-2564, 43, 2002.

111

Goossens J.-F., Henichart J.-P., Anizon F., Prudhomme M., Dugave

C., Riou J.-F., Bailly C., Cellular uptake and interaction with purified
membranes of rebeccamycin derivatives, Eur. J. Pharmacol., 141146, 389, 2000.

112

Arimondo P.B., Moreau P., Boutorine A., Bailly C., Prudhomme M.,
Sun J.-S., Garestier T., Helene C., Recognition and cleavage of DNA
by rebeccamycin- or benzopyridoquinoxaline conjugated of triple
helix-forming oligonucleotides, Bioorg. Med. Chem., 777-784, 8,
2000.

113

Arimondo P.B., Bailly C., Boutorine A., Moreau P., Prudhomme M.,
Sun J.-S., Garestier T., Helene C., Triple helix-forming
oligonucleotides conjugated to indolocarbazole poisons direct
topoisomerase I-mediated DNA cleavage to a specific site,
Bioconjug. Chem., 501-509, 12, 2001.

-249-

7:

114

Arimondo P.B., Helene C., Design of new anti-cancer agents based

on topoisomerase poisons targeted to specific DNA sequences, Curr.
Med. Chem. Anticancer Agents, 219-235, 1, 2000.

115

Yoshinari T,, Yamada A,, Uemura D,, Nomura K, Arakawa H,, Kojiri
K,, Yoshida E,, Suda H,, Okura A., Induction of topoisomerase Imediated DNA cleavage by a new indolocarbazole, ED-110, Cancer
Res., 490-494, 53, 1993.

116

Arakawa H., Iguchi T., Yoshinari T., Kojiri K., Suda H., Okura A., ED110, a novel indolocarbazole, prevents the growth of experimental
tumors in mice, Jpn. J. Cancer Res., 574-581, 84, 1993.

117

Yoshinari T., Matsumoto M., Arakawa H., Okada H., Noguchi K., Suda
H., Okura A., Nishimura S., Novel antitumor indolocarbazole
compound 6-N-formylamino-12,13-dihydro-1,11- dihydroxy-13-(-Dglucopyranosyl)-5H-indolo[2,3-a]pyrrolo[3,4-c]carbazole-5,7(6H)dione (NB-506): Induction of topoisomerase I-mediated DNA
cleavage and mechanisms of cell line-selective cytotoxicity, Cancer
Res., 1310-1315, 55, 1995.

118

Arakawa H., Iguchi T., Morita M., Yoshinari T., Kojiri K., Suda H.,
Okura A., Nishimura S., Novel indolocarbazole compound 6-Nformylamino-12,13-dihydro-1,11-dihydroxy13-(-Dglucopyranosyl)-5H-indolo[2,3-a]pyrrolo-[3,4-c]carbazole- 5,7(6H)dione (NB-506): its potent antitumor activities in mice, Cancer Res.,
1316-1320, 55, 1995.

119

Kanzawa F., Nishio K., Kubota N., Saijo N., Antitumor activities of a
new indolocarbazole substance, NB-506, and establishment of NB506-resistant cell lines, SBC-3/NB, Cancer Res., 2806-2813, 55,
1995.

120

Fukasawa K., Komatani H., Hara Y., Suda H., Okura A., Nishimura S.,
Yoshinari T., Sequence-selective DNA cleavage by a topoisomerase I
poison, NB-506, Int. J. Cancer, 145-150, 75, 1998.

121

Bailly C., Qu X., Chaires J.B., Colson P.,Houssier C., Ohkubo M.,
Nishimura S., Yoshinari T., Substitution at the F-ring N-imide of the
indolocarbazole antitumor drug NB-506 increases the cytotoxicity,
DNA binding, and topoisomerase I inhibition activities, J. Med.
Chem., 2927-2935, 42, 1999.

122

Ren J., Bailly C., Chaires J.B., NB-506, an indolocarbazole

topoisomerase I inhibitor, binds preferentially to triplex DNA, FEBS
Lett., 355-359, 470, 2000.

123

Urasaki Y., Laco G., Takebayashi Y., Bailly C., Kohlhagen G.,
Pommier Y., Use of camptothecin-resistant mammalian cell lines to
evaluate the role of topoisomerase I in the antiproliferative activity of
the indolocarbazole, NB-506, and its topoisomerase I binding site,
Cancer Res., 504-508, 61, 2001.

124

Facompre M., Goossens J.-F., Bailly C., Apoptotic response of HL-60

human leukemia cells to the antitumor drug NB-506, a glycosylated
indolocarbazole inhibitor of topoisomerase 1, Bioch. Pharmacol.,
299-310, 61, 2001.

-250-

8:

125

Ohe Y., Tanigawara Y., Fujii H., Ohtsu T., Wakita H., Igarashi T.,
Minami H., Eguchi K., Shinkai T., Tamura T., Kunotoh H., Saijo N.,
Okada K., Ogino H., Sasaki Y., Phase I and pharmacology study of
5-day infusion of NB-506, Proc. ACSO, 199a, 16, 1997.

126

Ohkubo M., Nishimura T., Jona H., Honma T., Morishima H.,
Practical synthesis of indolopyrrolocarbazoles, Tet., 8099-8112, 52,
1996.

127

Yoshinari T., Ohkubo M., Fukasawa K., Egashira S., Hara Y.,
Matsumoto M., Nakai K., Arakawa H., Morishima H., Nishimura S.,
Mode of action of a new indolocarbazole anticancer agent, J-107088,
targeting topoisomerase I, Cancer Res., 4271-4275, 59, 1999.

128

Bailly C., Dassonneville L., Colson P., Houssier C., Fukasawa K.,
Nishimura S., Yoshinari T., Intercalation into DNA is not required for
inhibition of topoisomerase I by indolocarbazole antitumor agents,
Cancer Res., 2853-2860, 59, 1999.

129

Arakawa H., Morita M., Kodera T., Okura A., Ohkubo M., Morishima
H., Nishimura S., In vivo anti-tumor activity of a novel
indolocarbazole compound, J-107088, on murine and human tumors
transplanted into mice, Jpn. J. Cancer Res., 1163-1170, 90, 1999.

130

Cavazos C.M., Keir S.T., Yoshinari T., Bigner D.D., Friedman H.S.,
Therapeutic activity of the topoisomerase I inhibitor J-107088 [6-N(1-hydroxymethyla-2-hydroxy)
ethylamino-12,13-dihydro-13-(-Dgluco pyranosyl)-5H-indolo[2,3-a]-pyrrolo[3,4-c]-carbazole-5,7(6H)dione] against pediatric and adult central nervous system tumor
xenografts, Cancer Chemother. Pharmacol., 250-254, 48, 2001

131

http://www.nci.nih.gov/search/clinical_trials/results_clinicaltrials
advanced.aspx

132

Horan A.C., Golik J., Matson J.A., Patel M.G., Antibiotics, Chem.
Abstr., 5184j, 105, 1986.

133

Matson J.A., Claridge C., Bush J.A., Titus J., Bradner W.T., Doyle
T.W., Horan A.C., Patel M., AT2433-A1, AT2433-A2, AT2433-B1, and
AT2433-B2: Novel antitumor antibiotic compounds produced by
Actinomadura melliaura. Taxonomy, fermentation, isolation and
biological properties, J. Antibiot., 1547-1555, 42, 1989.

134

Golik J., Doyle T.W., Krishnan B., Dubay G., Matson J.A., AT2433,A1, AT2433-A2, AT2433-B1 and AT2433-B2 novel antitumor
compounds produced by Actinomadura melliaura. II. Structure
determination, J. Antibiot., 1784-1789, 42, 1989.

135

Carrasco C., Facompre M., Chisholm J.D., Van Vranken D.L., Wilson
W.D., Bailly C., DNA sequence recognition by the indolocarbazole
antitumor antibiotic AT2433-B1 and its diastereoisomer, Nucleic
Acids Res., 1774-1781, 30, 2002.

136

Division of Cancer Department, NCI, Rebeccamycin analogue BMY27557-14, Clinical Brochure, Bethesda, MD, National Cancer
Institute, May 1995.

137

Merchant J., Tutsch K., Dresen A., Arzoomanian R., Alberti D., et al.,
Phase I clinical and pharmacokinetic study of NSC 655649, a

-251-

7:

rebeccamycin analogue, given in both single-dose and multiple-dose

formats, Clin.Cancer Res., 2193-2201, 8, 2002.
138

Krishnan B.S., Moore M.E., Lavoie C.P., Long B.H., Dalterio R.A.,
Wong H.S., Rosenberg I.E., Fluorescence polarization studies of the
binding of BMS 181176 to DNA, J. Biomol. Struct. Dyn., 625-636,
12, 1994.

139

Moreau P., Anizon F., Sancelme M., Prudhomme M., Bailly C., et al.,
Syntheses and biological evaluation of indolocarbazoles, analogs of
rebeccamycin, modified at the imide heterocycle, J. Med. Chem.,
1631-1640, 41, 1998.

140

Weitman S., Moore R., Barrera H., Cheung N.K., Izbicka E., Von Hoff
D.D., In vitro antitumor activity of rebeccamycin analog (NSC#
655649) against pediatric solid tumors, J. Pedriat. Hematol. Oncol.,
136-139, 20, 1998.

141

Tolcher A.W., Eckhardt S.G., Kuhn J., Hammond L., Weiss G., Rizzo
J., Aylesworth C., Hidalgo M., Patnaik A., Schwartz G., Felton S.,
Campbell E., Rowinsky E.K., Phase I and pharmacokinetic study of
NSC 655649, a rebeccamycin analog with topoisomerase inhibitory
properties, J. Clin. Oncol., 2937-2947, 19, 2001.

142

Dowlati A., Hoppel C.L., Ingalls S.T., Majka S., Li X., Sedransk N.,
Spiro T., Gerson S.L., Ivy P., Remick S.C., Phase I clinical and
pharmacokinetic study of rebeccamycin analog NSC 655649 given
daily for five consecutive days, J. Clin. Oncol., 2309-2318, 19, 2001.

143

Hussain M., Vaishampayan U., Heilbrun L.K., Jain V., LoRusso P.M.,
Ivy P., Flaherty L., A phase II study of rebeccamycin analog (NSC655649) in metastatic renal cell cancer, Invest. New Drugs, 465471, 21, 2003.

144

Bonjouklian R., Smitka T.A., Doolin L.E., Molloy R.M., Debono M.,
Shaffer S.A., Moore R.E., Stewart J.B., Patterson G.M.L.,
Tjipanazoles, new antifungal agents from the blue-green alga
Tolypothrix tjipanasensis, Tet.., 7739-7750, 47, 1991.

145

Corbett T.H., Pokn L., Wozniak A.J., Brssery M., LoRusso P.M,
Valenote F.A., Baker L.H., Proc. of Am. Assoc. Cancer Res., 533, 29,
1988.

146

Gilbert E.J., Van Vranken D.L., Control of Dissymmetry in the

Synthesis of (+)-Tjipanazole F2, J. Am. Chem. Soc., 5500-5501,
118, 1996.

147

Gilbert E. J., Ziller J.W., Van Vranken D.L., Cyclizations of

unsymmetrical
bis-1,2-(3-indolyl)ethanes:
Synthesis
of
(-)tjipanazole F1, Tet., 16553-16564, 53, 1997.

148

Shankar B.B., McCombie S.W., Indolocarbazoles. 4. Synthetic

studies towards staurosporine and tjipanazoles: Reactions of
indolocarbazole with glycals, Tet. Let., 3005-3008, 35, 1994.

149

Somei M., Yamada F., Kato J., Suzuki Y., Ueda Y., Chemistry of
indoles. 108. Short step syntheses of indolo[2,3-a]carbazoles
carrying an alkyl, allyl, or a glycosyl group at the 11-position and a
novel
6,7-dihydro-13H-cyclopentano[mn]indolo[3,2-c]acridine
derivative, Heterocycles, 81-84, 56, 2002.

-252-

8:

150

Stoltz B.M., Wood J.L., The stereoselective ring contraction of a

pyranosylated indolecarbazole. A biosynthetic link between K252a
and staurosporine?, Tet. Let., 3929-3930, 37, 1996.

151

Shankar B.B., McCombie S.W., Kirkup M.P., Viet A.Q., Puar M.S.,
Ganguly A.K., Indolocarbazoles. 2. Synthetic studies towards
staurosporine. An unexpected 1,2 migration of indolocarbazole
nitrogen results in a novel and potent Protein Kinase C inhibitor, Tet.
Let., 5685-5688, 34, 1993.

152

Stoltz B.M., Wood J.L., A ring expansion approach to pyranosylated

indolocarbazoles, Tet. Let., 8543-8544, 36, 1995.

153

Wood J.L., Stoltz B.M., Onwueme K., Goodman S.N., The synthesis
of desamido analogs of staurosporine, RK-286c, and TAN-1030a Tet.
Let., 7335-7338, 37, 1996.

154

Wood J.L., Stoltz B.M., Dietrich H.-J., Pflum D.A., Petsch D.T.,
Design and implementation of an efficient synthetic approach to
furanosylated indolocarbazoles: Total synthesis of (+)- and (-)K252a, J. Am. Chem. Soc., 9641-9651, 119, 1997.

155

Voldoire A., Moreau P., Sancelme M., Matulova M., Leonce S., Pierre
A., Hickman J., Pfeiffer B., et al., Analogues of antifungal
tjipanazoles from rebeccamycin, Bioorg. Med Chem., 1955-1962,
12, 2004.

156

Franck B., Gehrken H.P., Citreoviridins from Aspergillus terreus,

Angew. Chem., Int. Ed. Engl., 461-462, 19, 1980.

157

Kopanski L., Li G.R., Besl H., Steglich W., Fungus pigments. 41.
Naphthoquinone pigments from the slime molds Trichia floriformis
and Metatrichia vesparium (Myxomycetes), Liebigs Ann. Chem.,
1722-1729, 1982.

158

Trinks U., Buchdunger E., Furet P., Kump W., Mett H., Meyer T.,
Muller M., Regenass U., Rihs G., Lydon N., Dianilinophthalimides:
Potent and selective, ATP-competitive inhibitors of the EGF-receptor
protein tyrosine kinase, J. Med. Chem., 1015-1027, 37, 1994.

159

Sancelme M., Fabre S., Prudhomme M., Antimicrobial activities of

indolocarbazole and bis-indole protein kinase C inhibitors, J.
Antibiot., 792-798, 47, 1994.

160

Zhu G., Conner S.E., Zhou X., Shih C., Li T., Anderson B.D., et al.,
Synthesis, structure-activity relationship, and biological studies of
indolocarbazoles as potent cyclin D1-CDK4 inhibitors, J. Med. Chem.,
2027-2030, 46, 2003.

161

Slater M.J., Cockerill S., Baxter R., Bonser R.W., Gohil K., et al.,
Indolocarbazoles:
Potent,
selective
inhibitors
of
human
cytomegalovirus replication, Biorg. Med. Chem., 1067-1074, 7,
1999.

162

De Jong M.D., Galasso G.J., Gazzard B., Griffiths P.D., Jabs D.A.,
Kern E.R., Spector S.A., Summary of the Second International
Symposium on Cytomegalovirus, Antiviral Res., 141-162, 39, 1998.

-253-

7:

163

Hoffman V.F., Skiest D.J., Therapeutic developments in

cytomegalovirus retinitis, Expert. Opin. Invest. Drugs, 207-220, 9,
2000.

164

Van Zeijl M., Fairhurst J., Baum E.Z., Sun L., Jones T.R., The human
cytomegalovirus UL97 protein is phosphorylated and a component of
virions, Virology, 72-80, 231, 1997.

165

Desai B., Sureja D., Naliapara Y., Shah A., Saxena A.K., Synthesis
and QSAR Studies of 4-Substituted phenyl-2,6-dimethyl-3, 5-bis-N(substituted phenyl)carbamoyl-1,4-dihydropyridines as potential
antitubercular agents, Biorg. Med. Chem., 1993-1998, 11, 2001.

166

Zimmermann A., Wilts H., Lenhardt M., Hahn M., Mertens T.,
Indolocarbazoles exhibit strong antiviral activity against human
cytomegalovirus and are potent inhibitors of the pUL97 protein
kinase, Antiviral Res., 49-60, 48, 2000.

167

Schmidt J.V., Bradfield C.A., Ah receptor signaling pathways, Annu.

Rev. Cell. Dev. Biol., 55-89, 12, 1996.

168

McGuire J., Whitelaw M.L., Pongratz I., Gustafsson J.A., Poellinger L.,
A cellular factor stimulates ligand-dependent release of hsp90 from
the basic helix-loop-helix dioxin receptor, Mol. Cell. Biol., 24382446, 14, 1994.

169

Bjeldanes L.F., Kim J.Y., Grose K.R., Bartholomew J.C., Bradfield

C.A., Aromatic hydrocarbon responsiveness-receptor agonists
generated from indole-3-carbinol in vitro and in vivo: Comparisons
with 2,3,7,8-tetrachlorodibenzo-p-dioxin, Proc. Natl. Acad. Sci. USA,
9543-9547, 88, 1991.

170

Tholander J., Bergman J., Syntheses of 6-substituted indolo[3,2b]carbazoles, including 6-formylindolo[3,2-b]carbazole, an extremely
efficient ligand for the TCDD (Ah) receptor, Tet., 6243-6260, 55,
1999.

171

Rannug U., Rannug A., Sjoeberg U., Li,H., Westerholm R., Bergman
J., Structure elucidation of two tryptophan-derived, high affinity Ah
receptor ligands, Chem. Biol., 841-845, 2, 1995.

172

Wei Y.D., Helleberg H., Rannug U., Rannug A., Rapid and transient
induction of CYP1A1 gene expression in human cells by the
tryptophan photoproduct 6-formylindolo[3,2-b]carbazole, Chem.
Biol. Interact.,39-55, 110, 1998.

173

Tholander J., Bergman J., Syntheses of 6,12-disubstituted 5,11dihydroindolo[3,2-b]carbazoles, including 5,11-dihydroindolo[3,2b]carbazole-6,12-dicarbaldehyde, an extremely efficient ligand for the
TCDD (Ah) receptor, Tet., 12577-12594, 55, 1999.

174

Yudina L.N., Bergman J., Synthesis and alkylation of indolo[3,2b]carbazoles, Tet., 1265-1275, 59, 2003.

175

Bergman J., Wahlstrom N.,. Yudina L.N., Tholander J., Lidgren, G.,
Synthesis of indolocarbazole quinones; potent aryl hydrocarbon
receptor ligands, Tet., 1443-1452, 58, 2002.

176

Gillner M., Bergman J., Cambillau C., Alexandersson M., Fernstrom

B., Gustafsson J.A., Interactions of indolo[3,2-b]carbazoles and

-254-

8:

related polycyclic aromatic hydrocarbons with specific binding sites

for 2,3,7,8-tetrachlorodibenzo-p-dioxin in rat liver, Mol. Pharmacol.,
336-345, 44, 1993.
177

Balamurali R., Prasad K.J., Synthesis, characterization and

pharmacological
activities
of
5,6,11,12-tetrahydroindolo[2,3alpha]carbazole derivatives, Farmaco, 229-232, 56, 2001.

178

Chen A.Y., Yu C., Gatto B., Liu L.F., DNA minor groove-binding
ligands: a different class of mammalian DNA topoisomerase I
inhibitors, Proc. Natl. Acad. Sci. USA, 8131-8135, 90, 1993.

179

Kim J. S., Sun Q., Gatto B., Yu C., Liu A., Liu L.F., LaVoie E.J.,
Structure-activity relationships of benzimidazoles and related
heterocycles as topoisomerase I poisons, Bioorg. Med. Chem., 621630, 4, 1996.

180

Fujii N., Yamashita Y., Saitoh Y., Nakano H., Induction of

mammalian DNA topoisomerase I-mediated DNA cleavage and DNA
winding by bulgarein, J. Biol. Chem., 13160-13165, 268, 1993.

181

Wassermann K., Markovits J.,Jaxel C., Capranico G., Kohn K.W.,

Pommier Y., Effects of morpholinyl doxorubicins, doxorubicin, and
actinomycin D on mammalian DNA topoisomerases I and II, Mol.
Pharm., 38-45, 38, 1990.

182

Trask D.K., Muller M.T., Stabilization of type I topoisomerase-DNA

covalent complexes by actinomycin D, Proc. Natl. Acad. Sci. USA,
1417-1421, 85, 1988.

183

Sorensen B.S., Jensen P.B., Sehested M., Jensen P.S., Kjeldsen E.,
Nielsen O.F., Alsner J., Antagonistic effect of aclarubicin on
camptothecin induced cytotoxicity: role of topoisomerase I,
Biochem. Pharmacol., 2105-2110, 47, 1994.

184

Cummings J., Macpherson J.S., Meikle I., Smyth J.F., Development

of anthracenyl-amino acid conjugates as topoisomerase I and II
inhibitors that circumvent drug resistance, Biochem. Pharmacol.,
979-990, 52, 1996.

185

Cummings J., Hadfield J.A., Meikle I., McGown A.T., Smyth J.F.,
Molecular modeling of the interaction of anthracenyl-amino acid
topoisomerase inhibitors with the DNA sequence d(CGTACG),
Anticancer Drugs, 636-641, 7, 1996.

186

Beerman T.A., McHugh M.M., Sigmund R., Lown J.W., Rao K.E.,
Bathini Y., Effects of analogs of the DNA minor groove binder
Hoechst 33258 on topoisomerase II and I mediated activities,
Biochem. Biophys. Acta, 53-61, 1131, 1992.

187

Boothman D.A., Trask D.K., Pardee A.B., Inhibition of potentially

lethal DNA damage repair in human tumor cells by beta-lapachone,
an activator of topoisomerase I, Cancer Res., 605-612, 49, 1989.

188

Li C.J., Averboukh L., Pardee A.B., -Lapachone, a novel DNA

topoisomerase I inhibitor with a mode of action different from
camptothecin, J. Biol. Chem., 22463-22468, 268, 1993.

189

Frydman B., Marton L.J., Sun J.S., Neder K., Witiak D.T., Liu A.A.,
Wang H.M., Mao Y., Wu H.Y., Sanders M.M., Liu L.F., Induction of

-255-

7:

DNA topoisomerase II-mediated DNA cleavage by -lapachone and

related naphthoquinones, Cancer Res., 620-627, 57, 1997.
190

Schuerch A.R., Wehrli W., -Lapachone, an inhibitor of oncornavirus

reverse transcriptase and eukaryotic DNA polymerase-alpha.
Inhibitory effect, thiol dependence and specificity, Eur. J. Biochem.,
197-205, 84, 1978.

191

Ahn B.Z., Baik K.U., Kweon G.R., Lim K., Hwang B.D., Acylshikonin
analogues: Synthesis and inhibition of DNA topoisomerase-I, J. Med.
Chem., 1044-1047, 38, 1995.

192

Hecht S.M., Berry D.E., MacKenzie L.J., Busby R.W., Nasuti C.A., A
strategy for identifying novel, mechanistically unique inhibitors of
topoisomerase I, J. Nat. Prod., 401-413, 55, 1992.

193

Berry D.E., MacKenzie L., Shultis E.A., Chan J.A., Hecht S.M.,
Naturally occurring inhibitors of topoisomerase I mediated DNA
relaxation, J. Org. Chem., 420-422, 57, 1992.

194

Funabashi Y., Horiguchi T., Iinuma S., Tanida S., Harada S., TAN1496 A, C and E, diketopiperazine antibiotics with inhibitory activity
against mammalian DNA topoisomerase I, J. Antibiot., 1202-1218,
47, 1994.

-256-

/
.

,
.
.
,
,

.
,
,

:
1.

[2,3-a]

,
,
/ .


,
.

-259-

2.
,



.

-

.
3.
,
.

,

.

-260-

9:

1, 2
- (-excessive)
,
, . ,
. p

, .
. p
,
.
.
.
,
.

N
H

. ,
,
3 :
> > >

N
H

21, 29
16 Kcal/mol.
:

-263-

N
H

N
H

7:

N
H

N
H

N
H

67. .
,
.

. pKa 3.8,

(pKa=5.21)

(pKa=10.75).

N
H

,

. ,
- (-2). ,
,
,
- .

H
N
H

N
H

H
H

.
.
,

.

-264-

9:

N
H

Na
NaH
NaNH2

Na

CH3-MgI
N
H

CH4

BuH

N
MgI
BuLi
N
Li

68. .

,

. - ,

Wheland :

N
H

H
E

N
H

H
E

N
H

E
N
H

H
E

N
H

69. .
,
,
. 3, 2- ,
,
.

:

-265-

X
N

7:

O
X

N
H

X = Br, Cl

Br

Br
Br2
Br

Cl
N
H

HNO3
CH3COOH

RCN / HCl
H2O
Cl
N2

Cl

Cl

SO2Cl2

Br

N
H

N
H

Cl

N
H

NO2

N
H

COR

N
H

SO3H

N
SO3H

70.
.


.
N
Si(CH3)3

N
R
RX

(CH3)3SiCl
N

RCOCl

Na
RSO2Cl

N
COR

N
SO2R

N
MgI

N
H

CH3

71. .
1

March s Advanced Organic Chemistry, Reactions, Mechanisms, and

Structure, Smith M.B., March J. (Eds), 5th ed, A Wiley-Interscience
Publication, John Wiley & Sons, Inc., NY, 2001.

Eicher T., Hauptmann S., The Chemistry of Heterocycles, George

Thieme Verlag, New York, 1995.

Bird C.W., A new aromaticity index and its application to fivemembered ring heterocycles, Tet., 1409-1414, 41, 1985.

-266-

10:

10

2--

.

. ,

2-

1900. Oddo Moschini 1
2-- 90%
-

2--

ClCOOEt
N
MgBr

N
H

2
0 oC
35 oC

COOEt +

22%
3%

+
N
COOEt

N
COOEt +
COOEt

N
H

7%
13%

2%
26%

MgBrCl

42%
50%

72. 2--
2 o Grignard.
,
, Signaigo Adkins 2 1936,
2 22%, 7% 1-- 4, 2%
1,2--

5,

-267-

42%

10:

35 C,
0 C, ,
2 3%, 4 13%, 5
26%, 50% .
3, 4 , 5
Oddo Moschini, 2. Triebs Dietl 6
2 -
29%. Hodge
Rickards 7
48%.

Oddo Moschini ,
.

ClCOOEt
N
H

N
Li

1) ClCOOEt
N

2) KHCO3
O

73. 7
.

8
9,10

.
, 1963, Hodge Rickards7, 2- 8
Oddo
Moschini
11, 68% . , 2- 12,

11 ,
8, 82% .
,
94%
.

-268-

10:

, 12 ,

12 .

ClCOOCH3

N
MgBr
3

COOCH3+

N
H
9
20%

+
N
COOCH3

N
COOCH3
COOCH3

10

11

5-6%

64%

KOH
EtOH / H2O
RT, 2d
98%
POCl3
N
H

HCON(CH3)2

N
H

CHO

1) AgO
CH3OH / H2O

CH2N2
N
H

2) HCl

12

COOH

Et2O
94%

N
H

COOCH3

82% 1

74. 2--
.

,
2-- 66% 13 .
,

14 .
2-

-
15 . ,

, 78%14. ,


alumina. 1972, Bailey
16
(~3h)

-269-

10:

, 77-80%.

.
1 5%.
2-- 13
2- 91-92%.

1) CCl3COCl
Et2O

N
H

2) K2CO3

77-80%

Na
N
H

COCCl3

N
H

EtOH
91-92%

13

COOEt

75. 2--
2 .

2--

.

,

,
.

2-
.

2--

2,4-
, 2

2, 4-
2 , 17, 18 , 19 . ,

-270-

10:

20, 21 , 22 , Friedel-Crafts 23, 24 , 25 , 26

Friedel-Crafts 27,28 . 29
,
2,4- ,
Lewis.
, 2--

.
,

, 2-- 2

Friedel-Crafts.

Friedel-Crafts 2--
2 , ,

30 .
Lewis. 2 (1eq)
(2eq)
Lewis (2eq) 1,2-.
6

4--,

5--.

H3COC
CH3COCl (2 eq), Lewis acid (2 eq)

N
H

COOEt

N
H

ClCH2CH2Cl

14

-271-

COOEt

H3COC

N
H
15

COOEt

10:

6. Friedel-Crafts 2 Lewis.

Lewis

A/A
1
2
3
4
5
6
7

(C)

(h)

(%)

r.t.
r.t.
50
0
0
80
50

1.0
0.5
1.0
3 min
20 min
1.3
0.5

88.9
85.5
88.2
98.6
99.1
88.2
87.2

AlCl3
SbCl5
TiCl4
FeCl3
SnCl4
BF3.OEt2
ZnCl2

(14:15)
100:0
98:2
94:6
88:12
83:17
43:57
36:64

.
2 (2eq)

7
4- .

ROC
RCOCl (2 eq), AlCl3 (2 eq)

N
H

COOEt

N
H

ClCH2CH2Cl

COOEt

ROC

14, 16, 18,

20, 22, 24

N
H

COOEt

15,17,19,
21, 23, 25

7. Friedel-Crafts 2
AlCl3.
A/A

(C)

(h)

(%)

1
2
3
4
5
6

CH3
C3H7
ClCH2
4-MeO-C6H4
C6H5
4-NO2-C6H4

r.t.
75

80

1.0
2.5
1.0
2.5
2.5
2.0

99.9
86.7
47.2
78.0
71.7
78.3

14:15=100:0
16:17= 93:7
18:19=100:0
20:21= 91:9
22:23=100:0
24:25=100:0

.
4-- 14
,
. ,

5-- 15.

-272-

8.

10:

(eq 2) (C)

A/A
1
2
3
4
5

CH3COCl
(CH3CO)2O
(CH3CO)2O
CH3COCl
(CH3CO)2O

AlCl3 (2.0)
AlCl3 (2.0)
AlCl3 (6.0)
BF3.OEt2 (2.0)
BF3.OEt2 (2.0)

(CH3CO)2O

BF3.OEt2 (6.0)

(h)
(%)
(14:15)

r.t.
r.t.
0
80
r.t.
0
r.t.

1.0
6.0
0.25
1.25
1.5
0.5
0.5

88.9
80.6
92.9
88.2
88.0

100:0
88:12
100:0
43:57
53:47

89.3

48:52

, Friedel-Crafts 1--

(2eq)

26

(1eq).

4--

4--

5--,
2-,
5-.
4-.
H3COC
CH3COCl (2 eq), Lewis acid (2 eq)

N
COOEt
CH2Ph

N
COOEt
CH2Ph

ClCH2CH2Cl

26

H3COC

27

N
COOEt
CH2Ph
28

9. Friedel-Crafts 26 Lewis.
A/A

Lewis

T(C)

(min)

(%)

(27:28)

1
2
3
4

AlCl3
TiCl4
BF3.OEt2
ZnCl2

0
85
r.t.

20
20
55
80

81.8
89.6
80.7
95.8

100:0
100:0
77:23
65:35

-273-

10:

1-- 29 31 , ,
-
( 5- 2)
-.
. ,

- ,

- .
2 1-- -.

N
O2S

29

6 9,
Lewis,

4-

2-.

Lewis
,
- .
3 5 4
Friedel-Crafts.
Lewis Friedel-Crafts 2- 32
,
33 , (36.2% 2, 62.7% 4-
27.3% 5- 1- ).

-274-

N
H

10:

N
H

Cl

Al
Cl

N
H

Cl

Cl

Al

Al

Cl

Cl

Cl

Cl

Cl

76. 2--
2 AlCl3.

, 2,
4- .
, 1330, 34 2 ,
.
(2eq) (2eq), 1,2, (86-97%)
4- .
2-
2--4.

13 2
4,

2--4-

.
, 2

Friedel-Crafts .
2

13,

2-

-4-

2--4-

4-. ,
2-- 2
4- .

-275-

10:

,
2 (1eq) 35
(2eq), (6eq) 1,2-,

4--4-(2--4-)

30. , 2 (1eq)
3-

(2eq),

(4eq) 1,2-, 4-(3)

31,

92%.
(2eq)
4--
5--.

6 ,
- ,
.

3 ,
,
Lewis 2- ,
.
3-. 4 ,
,

2-
4 .

Friedel-Crafts,

, , 2 3 ,
35 4- 74%
5- 26%.

-276-

10:

5-
4-.

O
O

AlCl3 (6 eq)
ClCH2CH2Cl
87%

N
H

HOOC

N
H

COOEt

30

COOEt

Cl
COOCH3 (2 eq)
AlCl3 (4eq)
ClCH2CH2Cl
92%

H3COOC

N
H

COOEt

31

77. 4-- 2.

.
,


.

Fischer,
.
,

. -
, 2-() 3-()
36 .

-277-

10:

4- 37, 38 , 39 , 40 , 41 2() ,

, - -
, 1,4--7-4,5,6,7- 65% 42 .
1988 urakami Watanade 4 2-- 2

43

[f]

4--. ,

2,

, 1,2-, 2-[(5-3-)]

94%. 1996,

7--4,5,6,7-

3435

30,

4-.

Cl
N
H

COOEt

2
O

COOCH3 (2 eq)
AlCl3 (4eq)
ClCH2CH2Cl
92%

H3COOC

N
H
31

COOEt

(C2H5)3SiH
CF3COOH
RT, 24h
91%

30% H2SO4
CH3COOH
100 C, 20min
94%

AlCl3 (6 eq)
ClCH2CH2Cl
87%

H3COOC

N
H

COOEt

33

HOOC

N
H

30

COOEt

(CF3CO)2O

(C2H5)3SiH
CF3COOH
RT, 24h
73 %

HOOC

N
H
32

COOEt

CF3COOH
94%

N
H
34

COOEt

78. 34.
, - 30,
,
32. , - 31

-278-

10:

,
33. ,

32.

34. ,
- 30,

31 35.

O
CH3OH CH3CH2OH

HOOC

N
H

COOEt

30

. H2SO4
reflux, 1h, N2 atm

ROOC

N
H

COOEt

31, R = CH3 (96%)

35, R = CH3CH2 (98%)

79. - 31 35.

,

44 .
,

. ,
,
,
, .
,
-
32 34.
,
4- ,

.
4- , sp2 ,

-279-

10:

5- .
sp3

5-
.

34

.

34
6--7--4,5,6,7- 3635
. ,

,
3- 3735.

Br
O

N
H

COOEt

36

N
H

CuBr2
AcOEt
reflux, 1h, N2 atm.
89%

N
H

34

COOEt

Br
Br3

Pyridine
0 C, 30 min
86%

N
H

COOEt

37

80. - 36
37.

- 30 1,3 35. 1,2-

,
38.

,
,
39. ,

-280-

10:

40.

-
.
O

HOOC

N
H

30

COOEt

HSCH2CH2SH
BF3.OEt2
CH3COOH
RT, 9d
99%

HOOC

N
H

CH3OH
. H2SO4

COOEt

reflux, 1h, N2 atm

95%

38

H3COOC

N
H

COOEt

39

(CF3CO)2O
CF3COOH
44%

N
H

COOEt

40

81. 1,3-
.

Oddo B., Moschini A. Syntheses in the Pyrrole Group. VII.

Derivatives of -Pyrrolecarboxylic Acid and -Pyrrolecarboxylic Acid.
Gazz. Chim. Ital., 244-256, 42, II, 1912.

Signaigo FK., Adkins H., A Synthesis of dl-Proline from Pyrrole, J.

Am. Chem. Soc., 1122-1124, 58, 1936.

Andrews LH., McElvain SM., Gamma-pyrrolidino- and gammapyrrolinopropyl benzoates, J. Am. Chem. Soc., 887-892, 51, 1929.

Reichstein T., Aldehyde syntheses. Comparison of the three simplest

five-membered heterocyclic compounds, Helv. Chim. Acta, 349-356,
13, 1930.

Takeda R., Pseudomonas pigments. III. Derivatives of pyoluteorin,

Bull. Agric. Chem. Soc., Japan, 126-130, 23, 1959.

Treibs A., Dietl A., Constitution and reactions of alkali salts of

pyrrole. Annalen, 80-95, 619, 1958.

Hodge P., Richards R.W., Improved synthetic routes to pyrrole-2carboxylic acid and its derivatives. J. Chem. Soc., 2543-2545, 1963.

Smissman E.E., Graber M.B., Winzler R.J., The synthesis of pyrrole-2carboxylic acid. J. Amer. Pharmaceut. Assoc.(Sci. Edn), 509, 45,
1956.

-281-

10:

Letellier G., Bouthillier L.P., Synthesis of 2-pyrrolecarboxylic

(C14O2H) acid and study of its metabolism in the intact rat, Canad.
J. Biochem. Physiol., 811-817, 35, 1957.

10

Doyle F.P., Mehta M.D., Sach G.S., Pearson J.L., Pharmacodynamic

compounds. I. Some antispasmodics derived from substituted 2pyrrolidinylalkanols. J. Chem. Soc., 4458-4466, 1958.

11

Silverstein R.M., Ryskiewicz E.E., Willard C., Koehler R.C., Improved

synthesis of 2-pyrrolealdehyde and of n-methyl-2-pyrrolealdehyde.
further studies of pyrrole alcohols, J. Org. Chem., 668-672, 20,
1955

12

Nakano H., Umio S., Kariyone K., Tanaka K., Kishimoto T., Total
synthesis of pyrrolnitrin, a new antibiotic, Tet. Let., 737-740, 7,
1966.

13

Cooper W.D., Synthesis 2-Trifluoroacetylpyrrole, J.Org. Chem.,

1382, 23, 1958.

14

Treibs A., Kreuzer F.H., Electrophilic substitution of pyrroles with

acyl chlorides, Liebigs Ann. Chem., 105-115, 721, 1969.

15

Sanna G., Athene F., Polyhalogenated ketones. III. Pyrrole. Gazz.

Chim. Ital., 479-484, 63, 1933.

16

Bailey D.M., Johnson R.E., Albertson N.F.,

carboxylate, Org. Synt., 100-102, 51, 1971.

17

Anderson HJ, Pyrrole chemistry: I. Substitution reactions of 1methylpyrrole, Can. J. Chem., 21-27, 35, 1957.

18

Tirouflet J., Fournari P., Research in the heterocyclic series. VII.

Orientation of nitro derivatives of -substituted thiophenes, pyrroles,
and N-methylpyrroles, Bull. Soc. Chim. Fr., 1651-1654, 1963.

19

Anderson H.J., Pyrrole chemistry: II. 2-pyrrolecarbonitrile, 1-methyl2-pyrrolecarbonitrile, and their nitration products, Can. J. Chem.,
2053-2058, 37, 1959.

20

Hodge P., Rickards R.W., The halogenation of methyl pyrrole-2carboxylate and of some related pyrroles. J. Chem. Soc., 459-470,
1965.

21

Anderson H.J., Lee S.-F., Pyrrole chemistry: IV. The preparation and
some reactions of brominated pyrrole derivatives, Can. J. Chem.,
409-414, 43, 1965.

22

Farnier M., Fournari P., Heterocycles. XXI. Synthesis of pyrrolic

iodoaldehydes, Bull. Soc. Chim. Fr., 351-359, 1973.

23

Anderson H.J., Hopkins L.C., Pyrrole chemistry. III. Friedel-Crafts

isopropylation of methyl 2-pyrrolecarboxylate. Can. J. Chem., 12791287, 42, 1964.

24

Anderson H.J., Hopkins L. C., Pyrrole chemistry. V. Friedel-Crafts

isopropylations of some pyrrole derivatives. Can. J. Chem., 18311839, 44, 1966.

25

Anderson H.J., Huang C.W., Pyrrole chemistry. X. Friedel-Crafts

alkylation of some pyrrole and furan derivatives. Can. J. Chem.,
1550-1553, 48, 1970.

-282-

Ethyl

pyrrole-2-

10:

26

Groves J.K., Anderson H.J., Nagy H., Pyrrole chemistry. XIII. New
syntheses of 3-alkylpyrroles. Can. J. Chem., 2427-2432, 49, 1971.

27

Anderson H.J., Huang CW., Pyrrole chemistry. VI. Syntheses and

electrophilic substitution reactions of some 3-substituted pyrroles,
Can. J. Chem., 897-902, 45, 1967.

28

Anderson H.J., Riche C.R., Costello T.G., Loader C.E., Barnett G.H.,
Pyrrole chemistry. XIX. Reactions of 2-pyrrolecarbonitrile and its 4substituted derivatives, Can. J. Chem., 654-657, 56, 1978.

29

Anderson H.J., Loader C.E., The Synthesis of 3-Substituted Pyrroles

from Pyrrole, Synthesis, 353-364, 1985.

30

Tani M., Ariyasu T., Nishiyama C., Hagiwara H., Watanabe T.,
Yokoyama Y., Murakami Y., -Acylation of ethyl pyrrole-2carboxylate by Friedel-Crafts acylation: scope and limitations
(synthetic studies on indoles and related compounds. XXXVIII).
Chem. Pharm. Bull., 48-54, 44, 1996.

31

Masatoshi K., Hamel P., Frenette R., Rokach J., Regioselective

synthesis of acylpyrroles, J .Org. Chem., 3214-3219, 48, 1983.

32

Ishii H., Murakami Y., Fischer indolization and its related

compounds. XIII. Measurement of the nuclear magnetic resonance
spectra of ethyl indole-2-carboxylate derivatives using the shift
reagent and its application, Yakugaku Zasshi, 413-420, 99, 1979.

33

Murakami Y., Tani M., Suzuki M., Sudoh K., Uesato M., Tanaka K.,
Yokoyama Y., Synthetic studies on indoles and related compounds.
XII. A simple general method for the C-3 acylation of ethyl indole-2carboxylates, Chem. Pharm. Bull., 4707-4716, 33, 1985.

34

Blanger P., Electrophilic substitutions on 2-trichloroacetylpyrrole

Tet. Lett., 2504-2508, 20, 1979.

35

Tani M., Ariyasu T., Ohtsuka M., Koga T., Ogawa Y., Yokoyama Y.,
Murakami Y., New strategy for indole synthesis from ethyl pyrrole-2carboxylate (Synthetic studies on indoles and related compounds.
XXXIX), Chem. Pharm. Bull., 55-61, 44, 1996.

36

Sundeberg R. J., In: Katritzky A.R., Rees C.W., (Eds), Comprehensive

Heterocyclic Chemistry, Vol. 4, Pergamon Press, Oxford, 1984, pp.
348-370.

37

Yamashita A., Scahill T.A., Toy A., Reaction of a pyrrole-carbene

chromium complex with alkynes: A facile hydroindoloquinone
formation with in-situ protection. Tet. Lett., 2969-2972, 26, 1985.

38

Trost B.M., Reiffen M., Crimmin M. Thionium ions as reactive

carbonyl equivalents in cyclization reactions. J. Am.Chem. Soc., 257259, 101, 1979.

39

Natsume M., Muratake H., A carbon-carbon bond formation using an

endoperoxide of N-methoxycarbonylpyrrole and a convenient
synthesis of 4-alkylindoles. Tet. Lett., 3477-3480, 1979.

40

Fuji M., Muratake H., Natsume M., Preparation of alkyl-substituted

indoles in the benzene portion. Part 6. Synthetic procedure for 4-, 5-,
6-, or 7-alkoxy- and hydroxyindole derivatives. Chem. Pharm. Bull.,
2344-2352, 40, 1992.

-283-

10:

41

Matsumoto M., Ishida Y., Watanabe N., Selective halogenation of 4oxo-4,5,6,7-tetrahydroindoles

to
5-halo-4-oxo-4,5,6,7tetrahydroindoles with copper(II) halides. Heterocycles, 165-170,
23, 1985.

42

Harrowven D.C., Dainty R.F., A dichotomy in the Friedel-Crafts

reactions of lactones provides a convenient new route to 2-acylated
pyrroles and tetrahydroindolones. Tet. Lett., 6739-6742, 36, 1995.

43

Murakami Y., Watanabe T., Ishii H., Synthesis of linear ethyl 9methoxy-1H-benz[f]indole-2-carboxylate, J. Chem. Soc. Perkin
Trans I, 3005-3012, 1988.

44

West CT., Donnelly S.J., Kooistra D.A, Doyle MP., Silane reductions
in acidic media. II. Reductions of aryl aldehydes and ketones by
trialkylsilanes in trifluoroacetic acid. Selective method for converting
the carbonyl group to methylene, J. Org. Chem., 2675-2681, 38,
1973.

-284-

11:

11

1 .

-
,

,
, [a]-, [b]- [c]- -,
- -
a, b c . ,


.

[3,2].

N
H

N
H

X=O
X=S
X = NH

N
H

[3,2-a] [3,2-b]

[3,2-c]

82. [3,2].

1990

furostifoline,

[3,2-

a] .

-285-


, eustifoline-D, furoclausine
furoclausine B. ,
3,4 .

CH3

CH3
HO

N
H

CHO

N
H

Furostifoline

N
H

Eustifoline-D

N
H

Furoclausine A

OH

Furoclausine B

83. [3,2] .

, [a]-, -[b], [c]-
1990,
5,6 .
1980
7,8 , 9
10 ,
C 11 .

[2,3-c]

PYRAL-1, 2 3,
Dictyodendrilla sp.10

.

12

Borsche , Fischer

16,17

Diels-Alder

13, 14 , 15 ,

2-

3-

10, 18 , 19 , 20 , 21 , 22 , Diels-Alder
-2,3- 23, 24 , 25 DielsAlder 26 .

-286-

11:

NH

N
H
[2,3-c]

HO

H3COOC

OH

OH

HO

OH

O
N
N

OH

N
H

HO3SO

OH

OH
OH

N
H

RO

PYRAL-2, R = SO3Na
PYRAL-3, R = SO3H

PYRAL-1

84. [2,3-c] .

.
- 27 - 28 , - 29 - 30

DNA

31,32

N
H

N
S

N
H

N
H

N
H

-
N

N
H

N
H

N
H

N
H
-

85. -.

-287-

[a], [b], [c] [4,3] 33,34 .

 [4,3-b]
ellipticine
,
35,36 .

H3C

R1

N
H

N
H

CH3

CH3

CH3

Olivacine, R1 = H, R2 = Me
5-methyl-6H-pyrido[4,3-b]-carbazole-11methanol, R1 = CH2OH, R2 = H

Ellipticine, R = H
9-Methoxyellipticine, R = OMe
9-Hydroxyellipticine, R = OH

H
N

R2

H3C

H3C

N
H3C

CH3

N
H

CH3

Guatambuine, R = Me
Janetine, R = H

Strellidimine

86. Ellipticine .

Fischer
1883 o Emil Fischer F. Jourdan

1-

41 37 .

, o Fischer Hess
1-2- 42 38 .

CH3
N

CH3
N C
COOH

N
COOH
CH3

41

42

87. Fischer.

, ,

-288-

11:

Fischer,
.

.
Fischer

Fischer

, ,

R2C

O
R2C

H2N Y

O
NH2Y

R2C

H
O H

OH

R2C

NHY

H2O

NY
H
Y=

R2C NY

N
H

R
H2N Y =
R2C

O -

R2C NY =

88. .

Robinson Robinson 39 1924.
,
,
(NMR)

-289-

13

15

N 40,41 .


- 45 46.

-.
,
-, .
[3,3]-

.

, [3,3]
, -
42, 43 , 44 .

R2

R2

R1

R1

H
N
N
H
R
""
-
46

N
N
R

43
H

R2

R1

R2

N
R

N H
N
H
R

44
R1

H
N
H
N
H
R
48

R2

R1
N

N
R
47

""
-
45
R2

H
[3,3]

R1

R2
H R1

-H

H
H

R2
-NH3

N NH2

R1

N
R

R
49

50

89. Fischer Robinson

Robinson.

, 48,

49.

-290-

11:

45,46 .

15

50.

47 .

48 . ,
- [3,3]- .

---

. ,

[3,3]

42

[3,3]

,

-. [3,3]
,
.

Fischer
Fischer,

.
:
`

: - (p-TsOH)

49 (PPA) 50 .
`

51

.
`

: montmorillonite KSF

52 , (Mordenite ZeoliteY) 53 ,

-291-

 Amberlyst 15 54
.
Lewis: Baccolini 55

(PCl3)
70-90%.

.
,
- ,
11-37%. 3- ,

6-

3:2 Cl CH3 3:1

5:1 - 56 .
-, -, -, -,
PCl3
56.
PCl3 -
51 PCl3, -
53
Fischer,
Cl2PNH2 55
56 .
(diazaphospholes)

R2
R1CH2

N
HN

56, 57

PCl3

R2
R1CH2

R1

N
N
PCl2

-HCl

R2

R1

N
P
Cl

52
R1

N
N
PCl2 H

51
R2

Fischer
N
H

54

PCl2
R2
NH2

55

90. PCl3.

-292-

53
R1

-Cl2PNH2
N
H
56

R2

11:

(polyphosphoric acid trimethylsilyl ester, PPSE)
.

-
.
, .
:

-,

-. 57
HCl CH2Cl2 (indolenine)
58 -,
85% H2SO4 59 58 .

H3C

N
HN

Bz

CH3

CH3 H
N

57

H
N

Bz
+

HN

Bz

H
58

59

91.
.

:
.

41,

-, ,
59 .
:
2- 60 ,

-293-

 ,
60 .

HN N

60

61

62

R = CH3, C2H5,
i-Pr, t-Bu

92.
.

, NaNO2/HCl
.
,

Boc-,

Fischer,
61 .
3- . 3-
63 4- 6-
65 66 62 .
, -
6- 56,
-

4-

63 .
R

R2
+
R

NHNH2
63

93.

R1

R2
O
64

R1 +

N
H

R
65

R2
N
H
66

R1

3-

2- . 2-
3- 4-

-294-

64 .

11:

2-

-

62

,
. 62,
Cl- ( HCl )

65 .

R2

OCH3
N N
H

R2

N
H

R3

68

H3CO

R2

R2

R2
R3

R3
Nu

OCH3

67

H3CO

R3

H
Nu

N NH
H
69

N
H

NH2

N
H

Nu

70

R3

71

94. 2- .
- (
CH3), [1,2]
72 ,
74.
,
.
H3C

H3C

R2
R3

N NH
H

[1,2]

72

CH3

R2

R2

R3
N NH
H
73

N
H

R3

74

95. 2-

-295-

 -
CH3 CH3 2-
,
. , -
CF3 Cl

7665,66 .

triflate tosylate 67 .

Cl
N N
H3C

CH3

HCl

COOEt
N
CH3
76

EtOH

COOEt

Cl

33%

75

96. 2-
- .
.
- , ,

.


. 4-
2- ,

5-

68

69-76% .

a]

[2,3-

14

[2,3-a]

1- 77,
78,

-296-

79

11:

Fischer

1-[2,3-a]-2-

80.

,
,

.

O
1) NaNO2 / HCl
N
H

COOC2H5

2) SnCl2 / HCl
NH2

N
H

N
H

NH

Cl H3N

77

COOC2H5

79

78

N
H

CH3
HN

N
H

COOC2H5

80

97. [2,3-a]
80 1- 77.

34

[2,3-a]

Fischer

, - - .

NHNH2. HCl
R
N
H

N
H

COOC2H5

N
H

COOC2H5 +
R

R = Cl, Br,
CH3, CH3O

98. [2,3a] .

[2,3-a]

, [2,3a]

-297-

 Fischer.

34

-
.
( 10).

,
),

, [2,3-a]

10%.

N
H

COOEt

NHNH2 . HCl

+
R

34

H
p-CH3
p-CH3O
o-Cl
m-Cl
p-Cl

p-TsOH H2O
CH3COOH
H
R
N
H

N
H

COOEt

N
H

N
H

COOEt

10.
[2,3-a] .
A/A

34
(mmol)

(mmol)

p-TsOH
(mmol)

/ T

0.5

p-CH3 (1)

5.2 h, 80 C

0.5

p-OCH3 (1)

6.4 h, 80 C

0.5

o-Cl (1)

7.8 h, 80 C

0.5

m-Cl (1)

7.2 h, 80 C

0.5

p-OCH3 (1)

6.5 h, 80 C

0.5

H (1)

6.0 h, 80 C

0.5

H (1) ( HCl )

6.3 h, 80 C

-298-

11:

,

.

34 .

69
arcyriaflavins,
Fischer (HCl EtOH, BF3.OEt2
CH3COOH, PPA, H2SO4)
.
,


.



81,
(180-250 C)
, 70 .
,

82

(170 C) ( ) 71 .

R1
R2
N
H

R1

R1

N
H

81

R2

R2

83

N
H

COCH3

82

99. - .

, Naito 72

. N -

-299-

 84
85, , , ,
.
86

0 C 87.
[3,3]-

73 .

(one-pot reaction),
.
8873
89 74 .

R2

R3

R3
+
NH2
N
HCl
R1

84

85

R4

R3

R2

R4

MS 4

N
R1

R2

TFAA
(Et3N)

R4
N
R1

0 oC

86

COCF3

87

R3

R2

N
R1

R4

R2

100.

R4
N NHCOCF3
R1

88

R3

89

N-

.

,

90,
N- -. ,
34

4, 80100C, . ,
90, ,

-300-

11:

0 C
91.
0 C ,
100 C. ,
90%
.
[2,3-a]
. .

COOEt

N
H

34

HN

(CF3CO)2O

Et3N

CH3NO2

NH2 HCl

N
H

N2 atm

COOEt

N
H

Et3N

90

N2 atm

N
H

N
H

COOEt

COCF3
91

Refux, N2 atm

N
H

NH

COOEt

80

101. N- -
[2,3-a] .

.

75

. ,
, ,
,

, 30
.

N
H

34

COOEt

NHNH2 . HCl

CH3COONa

EtOHabs

Reflux, Ar

R
H
p-CH3
p-CH3O
o-Cl
m-Cl
p-Cl

-301-

R
N
H

N
H

92

COOEt

102.

34.
,
.

,

.

, .
,
93

94

N
H

O2N

COOEt

N
H

N
H

93

COOEt

N
H

94

103. .

.
.
,
,
.

, , ,
.

[2,3-a]

-302-

11:

Bergman

Pelcman,

69.

,

5,6--[()]-3,4,7,7-

-1,3- 95 N- ,

96

. ,

(polyphosphoric
acid trimethylsilyl ester, PPSE) ,
(CH3NO2) .

97 98,
,
[2,3-a][3,4-c] .
R
N

NHNH2.HCl
O

TMSO

N R
TMSO

R
N

O
H

CH3COOH / CH3OH

97

PPSE

CH3NO2
Ph N N
H

95

N N
H

N
H

N
H

Ph

R
N

96

O
H

Pd / C
DDQ

N
H

N
H
98

104. PPSE.

PPSE
PPSE , ,
.

-303-

99

(hexamethyldisiloxane,

HMDS)

- 103 76, 77 , 78 , PPSE

Immoto 1980,
Beckmann 79 .
Yamamoto Watanabe
PPSE
(NMR)

31

80

. PPSE ,

. PPSE

- 100,

, o
o 80.

O
P

O
O
O
O P O P
O
O P O
O
99

O
OTMS
P
O
O
O
O
P
P O
O
O P OTMS
TMSO
OTMS
47%
100,
-

(Me3Si)2O
CH2Cl2
80 oC, 24h

OTMS OTMS OTMS

P
P
P
TMSO
O
O
O
O
O
O

OTMS
P
OTMS
O

O
TMSO O P OTMS
O P
O
OTMS
O
P
P O O
O OTMS
26%
101,
-

OTMS OTMS
P
P
OTMS
O
TMSO
O
O

26%

1%

102,
-

103,
-

11. PPSE .
(%)

(C)

(h)

100

80

12

17

80

36

CH2Cl2

80

(ClCH2)2

A/A

101

102

103

33

46

26

59

36

52

29

15

80

24

47

26

26

80

24

18

60

21

PPSE
HMDS

-304-

11:

(, , , )
.
PPSE
,

Beckmann 82 ,

81 ,

Pummerer 83 ,

84

Meyer-

85

Schuster , ,
86 ,
87, 88 , 89 , 90
Friedel-Crafts 91 . ,

Fischer Yamamoto Watanabe
2--3-- 104
.

NHNH2
O
+

PPSE (4 eq)
ClCH2CH2Cl
85 oC, 10min,
88%

N
H
104

105. 104
PPSE.

PPSE PPA, ,

PPE (ethyl polyphosphate) 92,93 .
PPE
. PPSE,


Bergman
Pelcman.

[2,3-a]

[2,3-a] :
34

-305-

,
,
,
105(a-i). ,
, ,
PPSE (
)
. ,
106(a-i)
80(a-i).

N
H

AcONa

a=H
b = 4-CH3
c = 4-CH3O
d = 3-Cl
e = 2-Cl
f = 4-Cl
g = 3-Br
h = 2-Br
i = 4-Br

10

8
9

N
H

N
H

CH3NO2,

N
H

R
(a-i)

34

NHNH2. HCl

COOEt

+
COOEt

N
H

COOEt

105(a-i)

PPSE
H
H

CH3NO2,

H
H

R
N
H

80(a-i)

N
H

COOEt

106(a-i)

106. [2,3-a]
PPSE.

,
(high
performance liquid chromatography, HPLC). ,

H NMR.

2.8-3.0

. ,

-306-

11:

3-,
7 ,
7 .



,

.

-307-

11:

12. [2,3-a] .

SM (mmol)
Ar-NHNH2HCl (mmol)
AcONa (mmol)
CaCl2
CH3NO2 (ml)
T (C)/ (h)

H (1.4)

4-Cl (1.4)

4-CH3 (1.4)

3-Cl (1.4)

2-Cl (1.4)

4-CH3O
(1.4)

2-Br (1.4)

4-Br (1.4)

3-Br (1.4)

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

10

10

10

10

10

10

10

10

10

/3

/5

/2.5

/2.5

/2.5

75/4.75

/2

/2.5

/2.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

5.64

5.64

5.64

5.64

5.64

5.64

5.6

5.6

5.6

/3

/14

/6

/6

/20

70/11

/19

/6

/24

15

15

14

15

15

15

12

17

15

/4

/5

/4

/6

/7

/5

/4

/9

/6

PPSE
CH2Cl2 (ml)
P2O5 (mmol)
Me6Si2O (mmol)
Fischer
T (C)/ (h)

DDQ (mmol)
AcOEt (ml)
T (C)/ (h)

-308-

11:

70,94

,

[2,3-a]

.
, ,
,

-
70.


.

Cl
N
H

N
H

COOEt

106d

Pd/C 10% / dipentene

xylenes
reflux

Cl
N
H

N
H

N
H

N
H

COOEt

80a

COOEt

80d

107.
Pd/C 10%/
.

10% (Pd/C 10%)
. ,
( 137-144 C, 162 C)

3--

-309-

Pd/C

10%

11:

.
.

,
. ,
3-
2,3--5,6--1,4-

(2,3-dichloro-5,6-dicyano-

1,4-benzoquinone, DDQ) .


HPLC,
80d-1 80d-2.

Cl
N
H

N
H

COOEt

Cl
DDQ

106d

AcOEt
reflux

Cl
N
H

N
H

+
Cl

N
H

N
H

COOEt

N
H

COOEt

80d-2

80d-1

COOEt

N
H

80d

108.

DDQ.
:

-310-

Cl
Cl

N
H
H

DDQ
H
H

COOEt
N
H

NH

11:

Cl

H
COOEt

N
H

Cl

NH

N
H

H
OH

H
Cl

COOEt
+

Cl

OH

NH

N
H

109. DDQ.

.

,
12.

, ,
, -
. -. ,

.
3- 3--
,

, 6-
8- .

-311-

11:

N
H 105d, g

CH3NO2,

PPSE

R
6

R
6

+
R 8

N
N
H
H
106d, g-1

N
H

COOEt

COOEt

N
H

N
H

R 8

COOEt

N
H

106d, g-2

N
H

COOEt

80d, g-1

N
H

N
H

80d, g-2

DDQ
AcOEt

R = Cl, Br

reflux

110.
3-- .

3-

C-NH.
[3,3]-
- .

1,2/1, 8-
.

COOEt
R

111.

N
H

COOEt

N
H
N
H

N
H

4--

-312-

COOEt

11:

[2,3-a]
Fischer 3--7--4,5,6,7- (37)

,

Br
R
N
H

N
H

COOEt

107

[2,3-a]

3--7--4,5,6,7-
37,
7--4,5,6,7-
34.

3--

37,

PPSE ( )
.
,
,

-313-

11:

.
, DDQ
,
.

Br

Br
N
H

37

(a-i)

AcONa
CH3NO2,

N
H

N
H

a=H
b = 4-CH3
c = 4-CH3O
d = 3-Cl
e = 2-Cl
f = 4-Cl
g = 3-Br
h = 2-Br
i = 4-Br

N
H

+
COOEt

N
H

COOEt

108(a-i)

PPSE
H

Br
2

10

NHNH2. HCl

COOEt

H
H

R
N
H

107(a-i)

CH3NO2,

N
H

Br
COOEt

109(a-i)
DDQ
AcOEt
reflux

112.

3--[2,3-a]

-314-

11:

13. 3--[2,3-a] .

SM (mmol)
Ar-NHNH2HCl (mmol)
AcONa (mmol)
CaCl2
CH3NO2 (ml)
T (C)/ (h)

2-Br (1.4)

4-Br (1.4)

3-Br (1.4)

H (1.4)

4-Cl (1.4)

4-CH3 (1.4)

3-Cl (1.4)

2-Cl (1.4)

4-CH3O
(1.4)

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

5 gran

10

10

10

10

10

10

10

10

10

/1.5

/1.2

/1

/1.5

/1.2

/1.5

/1

/1

/0.75

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

3.5

5.64

5.64

5.64

5.64

5.64

5.64

5.6

5.6

5.6

/3

/2.5

/1.2

/3.5

/22

/1.2

/16

15

13

14

15

15

15

12

17

15

/4

/5

/7

/7

/7.5

/7.5

/7

/4h

/7

PPSE
CH2Cl2 (ml)
P2O5 (mmol)
Me6Si2O (mmol)
Fischer
T (C)/ (h)

/3

/5

DDQ (mmol)
AcOEt (ml)
T (C)/ (h)

-315-

11:

Kirsch G.H., Heterocyclic analogues of carbazole alkaloids, Curr.

Org. Chem., 507-518, 5, 2001.

Ito C., Furukawa H., New carbazole alkaloids from Murraya

euchrestifolia Hayata, Chem. Pharm. Bull. 1548- 1550, 38, 1990.

Hagiwara H., Choshi T., Nobuhiro J., Fujimoto H., Hibino S., Novel
syntheses of murrayaquinone A and furostifoline through 4oxygenated carbazoles by allene-mediated electrocyclic reactions
starting from 2-chloroindole-3-carbaldehyde. Chem. Pharm. Bull.,
881-886, 49, 2001.

Sos T., Timri G. and Hajs G., A concise synthesis of furostifoline,

Tet. Lett., 8607-8609, 40, 1999.

Basaveswara Rao M.V., Syam Kumar U.K., Ila H. and Junjappa H.

Synthesis and reactions of 2-bis(methylthio)methylene-1-methyl-3oxoindole: A facile access to benzo- and heterocyclo-fused carbazoles
and indoles, Tet., 11563-11578, 55, 1999.

Katritzky A.R. and Xie L., General and facile synthesis of

heterocyclo[b]-fused carbazoles, J. Org. Chem. 3707-3710, 60,
1995.

Takashi N., Isao M., Takashi F., Kenji O., Nobuhisa T., Masaaki S.,
Yosuke F., Hitoshi F., Takako H., Preparation of 1,2,3,5-tetrahydro1-oxopyrrolo[3,4-c] and [3,4-c]carbazole derivatives as anticancer
agents, Jpn. Pat. JP, 04230385/1992; Chem. Abstr., 124516x, 118,
1993.

Rao N.K.R., Stables J.R., Shannon P.V.R., Chunchatprasert L.,

Preparation of tetracyclic compounds as antitumor agents, PCT Int.
Appl. WO 9402 483/1994; Chem Abstr., 205330w, 121, 1994.

Sato A., Morishita T., Shiraki T., Yoshioka S., Horikoshi H., Kuwano
H., Hanzawa H. and Hata T., Aldose reductase inhibitors from a
marine sponge, Dictyodendrilla sp. J. Org. Chem., 7632-7634, 58,
1993.

10

Rotella D.P., Glicksman M.A., Prantner J.E., Neff N.T. and Hudkins
R.L., The effect of Pyrrolo[3,4-c]carbazole derivatives on spinal cord
ChAT activity, Biorg. Med. Chem. Lett., 1167-1170, 5, 1995.

11

Broka C.A., Preparation and formulation of pyrrolocarbazoles as

protein kinase C inhibitors, Eur. Pat. 695755, 1996, US Pat. Appl.
286043/1994; Chem. Abstr. 289516j, 124, 1996.

12

Samsoniya Sh.A., Kadzhrishvili D.O., Gordeev E.N., Suvorov N.N,

Pyrroloindoles. 10. Synthesis of some substituted pyrroloindoles and
tetrahydropyrrolocarbazoles, Khim. Geterotsikl. Soedin. 470-474, 4,
1984, Chem .Abstr., 72639s, 101, 1984.

13

Khoshtariya T.E, Sikharulidze M.I., Tret'yakova L.G., Efimova T.K,

Suvorov N.N., Pyrrolocarbazoles. 1. Synthesis and some properties
of 3H-pyrrolo[2,3-c]carbazole, Khim. Geterotsikl. Soedin., 790-793,
6, 1979, Chem .Abstr., 123652a, 91, 1979.

14

Sikharulidze M.I., Khoshtariya T.E., Kurkovskaya L.N., Tret'yakova

L.G., Efimova T.K., Suvorov N.N., Pyrrolocarbazoles. 3. Synthesis

-316-

11:

and spectral properties of 1H-pyrrolo[2,3-a]carbazole, Khim.

Geterotsikl. Soedin., 1362-1366, 10, 1979, Chem .Abstr., 146649q,
92, 1980.
15

Khoshtarya T.E., Sikharulidze M.I., Kurkovskaya L.N., Suvorov N.N.,

Pyrrolocarbazoles.
Synthesis
of
isomeric
pyrrolocarbazoles.
Soobshch. Akad. Nauk. Gruz. SSR, 97-100, 124, 1986. Chem. Abstr.,
217417d, 107, 1987.

16

Beccalli E.M., Marchesini A.,Pilati T.,Synthesis of [a]Annulated

Carbazoles from Indol-2(3H)-one, Synthesis, 891-894, 9, 1992.

17

Gramain J.C., Husson H.P., Troin Y., Stereospecific photochemical

synthesis
of
4a-substituted
trans-1,2,3,4,4a,9a-hexahydro-4carbazolones, Tet. Lett., 2323-2326, 26, 1985.

18

Pindur U., New Diels-Alder reactions with vinylindoles. A regio- and

stereocontrolled access to annellated indoles and derivatives,
Heterocycles, 1253-1268, 27, 1988.

19

Ziegler F.E., Spitzner E.B., and Wilkins C.K., Dimerization of 2-vinyl

indoles and their alcohol precursors, J. Org. Chem., 1759-1764, 36,
1971.

20

Saroja B., Srinivasan P.C., Synthesis and [4 + 2]-Cycloadditions of

N-Phenylsulfonyl-3-vinylindole, Synthesis, 748-749, 9, 1986.

21

Eitel M. and Pindur U., Reactions of 2-vinylindoles with

carbodienophiles: synthetic and mechanistic aspects, J. Org. Chem.,
5368-5374, 55, 1990.

22

Hudkins R.L., Knight E.Jr., Fused pyrrolocarbazoles useful for

enhancing the function/survival of neuronal cells and inhibition of
protein kinase, inflammation response, and hyperproliferative cell
growth, US Pat. 5475110/1995, Chem. Abstr. 202228v, 124,1996.

23

Pindur U., Haber M., Erfanian-Abdoust H., A one-pot access to

[b]annelated carbazoles as potential DNA intercalators via Diels-Alder
reactions with 1-alkylpyrano[3,4-b]indol-3-ones, Heterocycles, 781790, 34, 1992.

24

Drger M., Haber M., Erfanian-Abdoust H., Pindur U., Sattler K., New
potential DNA intercalators of the carbazole series from indole-2,3quinodimethanes: synthesis, crystal structure, and molecular
modeling with a Watson-Crick mini-helix, Monatsh. Chem. 559-576,
124, 1993.

25

Fray E.B., Moody C.J., and Shah P., 1,4-dihydropyrano[3,4-b]indol3-ones as precursors to indole-2,3-quinodimethanes, Tet., 439-450,
49, 1993.

26

Ciganek E. and Schubert E.M., Intramolecular Diels-Alder Reactions.

5. Approaches to the Pyrrolo[3,4-c]carbazole and Pyrido[4,3c]carbazole Systems1, J. Org. Chem., 4629-4634, 60, 1995.

27

Kansal V.K., Sundaramoorthi R., Das B.C., and Potier P., Nucleophilic
addition of aliphatic amino acids to N-2-methyl-9-hydroxyellipticinium acetate under peroxidase-catalysed oxidative conditions:
A reinvestigation and structural revision of the adducts, Tet. Lett.,
4933-4936, 26, 1985.

-317-

11:

28

Shanmugasundaram
K.,
Prasad
K.J.R.,
Synthesis
of
3phenylisoxazolo[3,4-a]carbazoles, Z. Naturforschung, B., 12021204, 54, 1999.

29

Chabane H., Lamazzi C., Thiry V., Guillaumet G. and Besson T.,
Synthesis of novel 2-cyanothiazolocarbazoles analogues of
ellipticine, Tet. Lett., 2483-2486, 43, 2002.

30

Achab S., Diker K. and Potier P., A short route to functionalized

imidazo[4,5-c]carbazoles. Synthesis of the first example of the
imidazo[4,5-c]-carboline ring system, Tet. Lett., 8825-8828, 42,
2001.

31

Pelaprat D., Oberlin R., Le Guen I., Le Pecq J.B., and Roques B.P.,
DNA intercalating compounds as potential antitumor agents. 1.
Preparation and properties of 7H-pyridocarbazoles, J. Med. Chem.,
1330-1335, 23, 1980.

32

Pindur U., Haber M., Sattler K., Intercalation model of cytostatics

with B-DNA, Pharm. Uns. Zeit, 21-36, 21, 1992.

33

Karmakar A.C., Kar G.K., Ray J.K., Efficient synthesis of 5-demethyl6-methylisoellipticine and utilization of the methodology to prepare
angular and linear pyridocarbazoles, J. Chem. Soc., Perkin Trans. 1,
1997-2002, 8, 1991.

34

Molina P., Fresneda P.M. and Almendros P., Fused carbazoles by

tandem Aza Wittig/electrocyclic ring closure. Preparation of 6Hpyrido[4,3-b] carbazole, 11H-pyrido[4,3-a]carbazole and 11Hpyrido[3,4-a]carbazole derivatives, Tet., 1223-1236, 49, 1993.

35

Dalton L.K., Demerac S., Elmes B.C., Loder J.W., Swan J.M., Teitei T.,
Synthesis of the tumor-inhibitory alkaloids, ellipticine, 9methoxyellipticine, and related pyrido[4,3-b]carbazoles, Aust. J.
Chem., 2715-2727, 20, 1967.

36

Van-Bac N., Moisand C., Gouyette A., Muzard G., Dat-Xuong N., Le
Pecq J.B., Paoletti C., Metabolism and disposition studies of 9hydroxyellipticine and 2-methyl-9-hydroxyellipticinium acetate in
animals. Cancer Treat. Rep., 879-887, 64, 1980.

37

Fischer E., Jourdan F.,Mittheilungen Ueber die Hydrazine der

Brenztraubensure, Ber., 2241-2245, 16, 1883

38

Fischer E., Hess O., Synthese von Indolderivaten, Ber., 559-568,

17, 1884.

39

Robinson G.M., Robinson R., Mechanism of E. Fischer's synthesis of

indoles. Application of the method to the preparation of a pyrindole
derivative, J. Chem. Soc., Trans., 827-840, 125, 1924.

40

Becker A.R., Janusz J.M., and Bruice T.C., Solution chemistry of the
syn- and anti-tetrahydrodiol epoxides, the syn- and antitetrahydrodimethoxy epoxides, and the 1,2- and 1,4-tetrahydro
epoxides of naphthalene, J. Am. Chem. Soc., 5676-5687, 101,
1979.

41

Hughes D.L. and Zhao D., Mechanistic studies of the Fischer indole
reaction, J. Org. Chem., 228233, 58, 1993.

-318-

11:

42

Prshevalskii N.M., Kostromina L.Y., Grandberg I.I., Mechanism of

the Fischer reaction. Effect of electronic factors on the rearrangement
kinetics
of
m-substituted
cyclohexanone
arylhydrazones
to
tetrahydrocarbazoles, Khim. Geterotsikl. Soedin., 1207-1212, 9
1985.

43

Vysotskii Y.B., Prshevalskii N.M., Zemskii B.P., Grandberg I.I.,

Kostromina L.Y., Mechanism of the Fischer indole synthesis.
Quantum chemical treatment of the rearrangement of cyclohexanone
arylhydrazones to tetrahydrocarbazoles, Khim. Geterotsikl. Soedin.,
898-907, 7, 1986.

44

Prsevalskii N.M., Kostromina L.Y., Grandberg I.I., Mechanism of the

Fischer reaction. Dependence of cyclohexanone arylhydrazone
thermal indolization rate on the nature of the substituent in the
benzene ring, Khim. Geterotsikl. Soedin., 188-192, 2, 1988.

45

Southwick P.L., Vida J.A., Fitzgerald B.M., and Lee S., 1-Carbamoyland
1-aminomethyl-1,4-dihydropyrrolo[3,4-b]indole
derivatives.
Indole formation by fragmentation of strain-barrier stabilized 2aminoindoline derivatives, J. Org. Chem., 2051-2056, 33, 1968.

46

Forrest T.P., Chen F.M.F., Isolation of a 2-aminoindoline derivative.

Suggested intermediate in the Fisher indole synthesis, J. Chem.
Soc., Chem. Commun., 1067, 19, 1972.

47

Clausius K., Weisser H.R., Reactions with nitrogen15. III. Mechanism

of the Fischer indole synthesis, Helv. Chim. Acta, 400-406, 35,
1952.

48

Hughes D.L., Progress in the Fischer indole reaction. A review., Org.

Prep. Proced. Int., 607-632, 25, 1993.

49

Yokoyama Y., Okuyama N., Iwadate S., Momoi T. and Murakami Y.,
Synthetic studies of indoles and related compounds. Part 22. The
VilsmeierHaack reaction of N-benzyl-1,2,3,4-tetrahydrocarbazoles
and its synthetic application to olivacine and ellipticine, J. Chem.
Soc., Perkin Trans. 1, 1319-1329, 5, 1990.

50

Guy A., Guette J. P., Lang G., Utilization of polyphosphoric acid in the
presence of a cosolvent. Synthesis, 222-223, 3, 1980.

51

Willard M.W., Pyridine hydrochloride-catalyzed

reactions, Synthesis, 645-646, 9, 1977.

52

Prochazka M.P., Eklund L., Carlson R., Zeolites as catalysts in the

Fischer indole synthesis. Enhanced regioselectivity for unsymmetrical
ketone substrates, Acta Chem. Scand., 610-613, 44, 1990.

53

Prochazka M.P., Carlson R., One-pot Fischer indole synthesis by

zeolite catalysis, Acta Chem. Scand., 614-616, 44, 1990.

54

Murakami Y., Yokoyama Y., Miura T., Hirasawa H., Kamimura Y.,
Izaki M., p-Toluenesulfonic acid and cation-exchange resin in aprotic
solvent: valuable catalysts for Fischer indolization, Heterocycles,
1211-1216, 22, 1984.

55

Baccolini G., Dalpozzo R. and Todesco P.E., Indolization by

phosphorus trichloride of functionalized ketone arylhydrazones:

-319-

Fischer

indole

11:

synthesis of pharmacological interesting indoles, J. Chem. Soc.,

Perkin Trans. 1, 971-973, 4, 1988.
56

Baccolini G., and Marotta E., Substituent influence on the

indolization with PCl3 of some o,m,p-substituted phenylhydrazones,
Tet., 4615-4620, 41, 1985.

57

Baccolini G., Dalpozzo R. and Errani E., Role of phosphorus adducts

in the indolization reaction between arylhydrazones and phosphorus
trichloride, Tet., 2755-2760, 43, 1987.

58

Freter K., Fuchs V., and Pitner T.P., Fischer indole synthesis from
cis- and trans-hexahydro-7-methyl-6-isoquinolones. Proton NMR
determination of the configuration and conformation of products, J.
Org. Chem., 4593-4597, 48, 1983.

59

Haelters J.P., Corbel B., Sturtz G., Synthesis of indolephosphonates

by Fischer cyclization of phosphonate arylhydrazones, Phosphorus
Sulfur, 41-63, 37, 1988.

60

Miller F.M. and Schinske W.N., Direction of cyclization in the Fischer

indole synthesis. Mechanistic considerations, J. Org. Chem., 33843388, 43, 1978.

61

Ashton P.R., Bissel R.A., Gorski R., Philip D., Spenser N., Stoddart
J.F., Tolley M.S., Towards controllable molecular shuttles. 2., Syn.
Lett, 919-922, 11, 1992.

62

Robinson B., The Fischer Indole Synthesis, J. Wiley & Sons, New
York, NY, 1982, p. 172-191.

63

Grandberg I.I., Belyaeva L.D., Dmitriev L.B., Indoles. XXVI. Ratios of

indole isomers formed during the Fischer cyclization of m-substituted
phenylhydrazones of diethyl ketone, Khim Geterotsikl, 1201-1203,
7, 1971.

64

Robinson B., The Fischer Indole Synthesis, J. Wiley & Sons, New
York, NY, 1982, p. 749-752.

65

Ishii H., Nucleophilic displacement of the methoxy group in abnormal

Fischer indolization of 2-methoxyphenylhydrazone, Acc. Chem. Res.,
275-283, 14, 1981.

66

Ishii H., Murakami Y., Ishikawa T., Abnormal Fischer indolization and
its related compounds. XXII. Fischer indolization of ethyl pyruvate 2(2-chloro- and 2,6- ichlorophenyl) methylhydrazones, Chem. Pharm.
Bull, 597-604, 38, 1990.

67

Murakami Y., Takahashi H., Nakazawa Y., Koshimizu M., Watanabe T.

and Yokoyama Y., The improved synthesis of 7-oxygenated indoles
by Fischer indolization and its application to the first total synthesis of
eudistomidin-A, Tet. Lett., 2099-2100, 30, 1989.

68

Fludzinski P., Wittenauer L.A., Schenck K.W., and Cohen M.L., 2,3Dialkyl(dimethylamino)indoles: interaction with 5HT1, 5HT2, and rat
stomach fundal serotonin receptors, J. Med. Chem., 2415-2418, 29,
1986.

69

Bergman J. and Pelcman B., Synthesis of indolo[2,3-a]pyrrolo[3,4c]carbazoles by double Fischer indolizations, J. Org. Chem., 824828, 54, 1989.

-320-

11:

70

Fitzpatrick J.T., and Hiser R.D., Notes-Noncatalytic Fischer indole

synthesis, J. Org. Chem., 1703-1704, 22, 1957.

71

Schiess P., Sendi E., The Fischer indole reaction. II. Thermal and
acid
catalyzed
indolization
of
1'-alkenyl-2'-methyl-2'phenylacetohydrazides, Helv. Chim. Acta, 1364-1372, 61, 1978.

72

Miyata O., Kimura Y., Muroya K., Hiramatsu H. and Naito T.,
Thermal cyclization of N-trifluoroacetyl enehydrazines under mild
conditions: A novel entry into the Fischer indole synthesis, Tet. Lett.,
3601-3604, 40, 1999.

73

Miyata O., Kimura Y., Naito T., One-pot synthesis of indoles from
ketones and hydrazines under mild reaction conditions, Synthesis,
1635-1638, 11, 2001.

74

Miyata O., Kimura Y., Naito T., Unambiguous characterization of

dienylimines as intermediates in Fischer indolisation of o-substituted
N-trifluoroacetyl enehydrazines, Chem. Commun., 2429-2430, 1999.

75

Vogel A.I., Tatchell A.R., Furnis B.S., Hannaford A.J., Smith P.W.G.,
Vogel s Textbook of Practical Organic Chemistry, 5th ed, John Wiley &
Sons Inc., New York, 1989, p. 1258.

76

Sauer
R.O.,
Derivatives
of
the
methylchlorosilanes.
I.
Trimethylsilanol and its simple ethers, J. Am. Chem. Soc., 17071710, 66, 1944.

77

Voronkov M.G., Silico.ovrddot. organic esters of phosphoric acidtris(trialkylsilyl) phosphates, Zh. Obshch. Khim., 437-438, 25, 1955.

78

Mileshkevich V.P., Karlin A. V., Reaction of hexamethyldisiloxane

with phosphorus(V) and boron(III) oxides, Zh. Obshch. Khim., 25732577, 40, 1970.

79

Imamoto T., Yokoyama H. and Yokoyama M., Trimethylsilyl

polyphosphate (PPSE), a useful reagent for the Beckmamn
rearrangement, Tet. Lett., 1803-1804, 22, 1981.

80

Yamamoto K., Watanabe H., Composition of polyphosphoric acid

trimethylsilyl ester (PPSE) and ist use as a condensation reagent,
Chem. Lett., 1225-1228, 8, 1982.

81

Imamoto T., Matsumoto T., Yokoyama H., Yokoyama M., and

Yamaguchi K., Preparation and synthetic use of trimethylsilyl
polyphosphate. A new stereoselective aldol-type reaction in the
presence of trimethylsilyl polyphosphate, J. Org. Chem., 1105-1110,
49, 1984.

82

Gawley R.E. and Termine E.J., The oxime rearrangement cyclization.

Synthesis of alkylidene-1-pyrrolines, J. Org. Chem., 1946-1951,
49, 1984.

83

Kakimoto M., Imai Y., Pummerer rearrangement promoted by

polyphosphoric acid trimethylsilyl ester (PPSE), Chem. Lett., 18311834,10, 1984.

84

Yoshimatsu M., Naito M., Kawahigashi M., Shimizu H., and Kataoka
T., Meyer-Schuster rearrangement of -sulfur-substituted propargyl
alcohols: A convenient synthesis of .alpha.,.beta.-unsaturated
thioesters, J. Org. Chem., 4798-4802, 60, 1995.

-321-

11:

85

Yokoyama M., Yoshida S., Imamoto T., Organic reactions using

trimethylsilyl polyphosphate (PPSE): A convenient synthesis of nitriles
from carboxamides, Synthesis, 591-592, 1982.

86

Imamoto T., Matsumoto T., Kusumoto T., Yokoyama M., A

convenient method for the preparation of alkyl iodides from alcohols,
Synthesis, 460-461, 6, 1983.

87

Mueller
C.E.,
Formation
of
oxazolo[3,2-a]purinones
propynyluracils, J. Org. Chem., 1928-1929, 59, 1994.

88

Bennasar M.-L., Vidal B., Lzaro A., Kumar R. and Bosch J., A short
route for the construction of the tetracyclic ring system of silicinemethuenine alkaloids, Tet. Lett., 3541-3544, 37, 1996.

89

Garca M.B., Orelli L.R., Magri M.L., Perillo I.A., An efficient

synthesis of 2,3-dihydro-1h-pyrimido[1,2-a]quinoxaline 6-oxides,
Synthesis, 2687-2690, 18, 2002.

90

Gawley R.E., and Chemburkar S., Generation and cyclization of

nitrilium ions from amides. Asymmetric synthesis of fused
azabicyclics, Tet. Lett., 2071-2074, 27, 1986.

91

Li W. and Fuchs P.L., Polyphosphoric Acid trimethylsilyl ester

promoted intramolecular acylation of an olefin by a carboxylic acid:
Convenient construction of C-18-functionalized 14-hecogenin
acetate, Org. Lett., 4061-4064, 5, 2003.

92

Pollman W., Schramm G., Reactivity of metaphosphate esters

prepared from P4O10 and ethyl ether, Biochem. Biophys. Acta, 1-7,
80, 1964.

93

Cava M.P., Lakshmikantham M.V., and Mitchell M.J., Synthesis of

caseadine methyl ether, J. Org. Chem., 2665-2666, 34, 1969.

94

Royer H., Joseph D., Prim D., Kirsch Gilbert., Synthesis of

pentacyclic heteroaromatic systems related to indolocarbazole
alkaloids. Synth. Commun., 1239-1251, 28, 1998.

-322-

from

12:

12

.


,

- .

,
,

,
,
,
.
,

34

,
.

, -

-323-

12:

Fischer.


Fischer.
.

.
.

.
,
.

4-(2--4-

) (30)

30, Beckmann
.

.
HO

HOOC

N
H

COOEt

HOOC

30

N
H

COOEt

110

14. - 30.
A/A

-
30 (eq)

H2NOH
(eq)

1.5

1.5

(eq)
Pyridine
(10)
AcONa
(1.5)
AcONa
(1.5)

-324-

(v/v)

T(C)/
(h)

(%)

EtOH abs

/6.5

71

EtOH abs

60/22

68

EtOH/H2O
(96/4)

60-5/7

56

12:

110,
.

/ 7/3)
.

H-NMR, , ,

.

, .
,
- 31 35.
,
35,

111. ,

, ,
. ,
,
. 1H-NMR.

HO

O
H2NOH HCl (1.5eq)
CH3COONa (1.5 eq)
EtOOC

N
H
35

COOEt

EtOH / H2O
(28/1)
Reflux, 3.5h
57%

EtOOC

N
H
111

COOEt

113. 35.

-325-

12:

112.

OH

H2NOH HCl (1.5eq)

CH3COONa (1.5 eq)
EtOOC

N
H

COOEt

EtOH / H2O
(7/1)
Reflux, 3.5h
91%

35

EtOOC

N
H

COOEt

112

114. syn- 35.

syn
,
.

syn
113 31,
.

H2NOH HCl (1.5eq)

CH3COONa (1.5 eq)
MeOOC

COOEt

N
H
31

EtOH / H2O
(7/1)
Reflux, 6h
88%

MeOOC

OH

N
H

COOEt

113

115. syn- 31.

Beckmann

4-(3-

)-2- (113)
113
Beckmann
.
Beckmann.
,
1,4- 113,

-326-

12:

,
( 15, / 1).

(/ 2). ,

1,2 ,
(/ 3).

OH

H
N
Beckmann

MeOOC

N
H

COOEt

Rearrangment

MeOOC

N
H

COOEt

15. Beckmann 113.

A/A

113
(eq)

(eq)

SOCl2 (2)

SOCl2 (120)

0.5

PPA 85%

1,4
1,4
-

T(C)/
(h)
r.t/2
r.t./2.5
100/1.2
110/10 min

(%)

Beckmann.
,

,

,
. ,
.

-327-

12:

4--

31,

4-[2-(1,3-)]-7--4,5,6,7--

40. 1,3-

Beckmann
7
, .

N
H

COOEt

40

X Y

COOEt

N
H

X Y

N
H

COOEt

X = -NH-, Y = -COX = -CO-, Y = -NH-

116.
40.

114a 114b, syn anti
.
.

H2NOH HCl (1.5eq)

CH3COONa (1.5 eq)
N
H
40

COOEt

EtOH / H2O
(10/1)
Reflux, 3.5h
86%

COOEt
N
H
N
OH
114a

(1 : ~1.9)

-328-

HO

N
H
114b

COOEt

12:

117.
40.

. ,

,
Beckmann.

,

.
,

syn 114a
0 C
115,
, .

SOCl2 (2eq)
N

N
COOEt
H
OH
114a

THF
0 C, 4.5h, N2 atm

N
H

COOEt

115

118. Beckmann 114a.

,
,
.

Fischer 4-[2-(1,3-)]-7-4,5,6,7-- (40)

-329-

Fischer

12:

4-[2-(1,3-)]-7--4,5,6,7-

- 40

[2,3-a].
,
,
116
. ,

PPSE

, 117.

NHNH2.HCl
S

PPSE
N
H

CH3COONa
CH3NO2
2.5 h, reflux, N2 atm

COOEt

40

N
H

N
H

COOEt

CH3NO2
2.5 h, , N2 atm

NH

116

N
H

COO
Et

117

119. Fischer
40.

PPSE,

,
.

1,3- 4-[2-(1,3)]-7--4,5,6,7-- (40)

40

-330-

12:

1,3-
.
.

N
H

COOEt

N
H

40

COOEt

118

16. 40.
A/A

40
(eq)

(eq)

(v/v)

Tl(NO3)3 3H2O
(2.4)
CuCl2 (2)
CuO (4)
CuCl2 (2)
CuO (4)

MeOH/THF
2.5/1
Acetone-H2O
(99/1)
Acetone-H2O
(99/1)

T(C)/
(h)

(%)

0/2

r.t./19

r.t./3

3 (A/A 1).
/ 40,
,
.

.

.


(A/A 2, 3) 4

,
. ,

-331-

12:

,

-
.

,
.

Bardakos V., Sucrow W., Enehydrazines, 22. Lactams from 1,5,6,7tetrahydro-4H-indol-4-ones, Chem. Ber., 1780-1788, 111, 1978.

Martinez R., Avila-Zarraga J.G., Lopez-Lopez G., Nava-Salgado V.O.,

Synthesis of the new triheterocyclic system C3N-C4N-C6N. 3-Aryl2,5,5-trimethyl-9a-methylsulfanyl-9-phenoxy-4,5,6,8,9,9ahexahydro-3H-azeto[1,2-a]pyrrolo[3,2-c]azepin-8-ones,
Heterocycles, 557-570, 53, 2000.

Greene T.W,. Wuts P.G.M, Protective Groups n Organic Synthesis, 3rd

ed., J. Willey & Sons, USA, 1999 p. 337.

Corey E.J. and Erickson B.W., Oxidative hydrolysis of 1,3-dithiane

derivatives to carbonyl compounds using N-halosuccinimide
reagents, J. Org. Chem., 3553-3560, 36, 1971.

-332-

12:

13

(-,

-,

-)

.


.

1-,

2-, 3-, ,
1,2 . ,

. ,
,
. ,
, ,
(NaH, KH), (NaNH2)
(NaOH, KOH) 3, 4 .

(),
- 5 .

6, 7 , 8 , 9 .
,
,
.
(t-C4H9)
2. t-C4H9,

-333-

13:

10 . 2- 2-
3. (diethoxymethyl,
DEM)
(triethyl orthoformate) 11 .

Cl
O

Si

-, BOC

2--

SO2
O

Si
-

O
Si

[2-()]-, SEM

-, POM

120.
.
-

(, NaH, NaOH)

2, 12 , 13 , 14 , 15 , 16 .

17

18

19,20 , 21

22 o 23 ,
.
, [2-()]

(SEM) 24 ,

(POM) 25

-334-

12:

(BuLi 26,27 ,

NaNH2 28 ,

NaH 29 )

-, -. ,

30

. ,

,

31,32 .

33

34

35

, , ,
.

,
,
.

.
,

34.

-335-

13:

,
.
, K2CO3,
(NaH 80% , KH 35% ) ,

(,

THF,

, DMF), ,
,

SO2Cl

N
H

COOEt

N
O O2S

, 2 atm

34

COOEt

119

17. 34
.

34
(eq)

(eq)

PhSO2Cl
(eq)

T (C)

34
(%)

1.5

r.t./60

90h

DMF

64

57

r.t./102

6.6d

DMF

58

r.t./

27h

THF

60

r.t./53

4d

DMF

55

1.5

40

48h

DMF

71

NaH
(1.2)
K2CO3
(46)
K
(0.417)
KH 35%
(1.5)
KH 35%
(1.5)

34
.

,
,
.

-336-

12:

.
,

121.
34.

2--

(2)

2
. ,
2,
. ,

24 .

2-

65%.

SO2Cl
KH 35%
N
H
2

COOEt

N
O2S
DMF
RT, 24h
65%

COOEt

120

122. 2
.

-337-

13:

4-[2-(1,3-)]-4-(2--4-) (39)
39
2 ( 18).


,
(/ 1).

- (/
2). , ,
18---6
,
121 56%,

(/

3).

,
,
. ,

,
,
.

H3COOC

t- BuOK
18-Crown-6

N
H

SO2Cl

H3COOC

COOEt
THF, rt, 2 atm

39

N
O2S
121

-338-

COOEt

12:

18. 39
.

A/A

39
(eq)

(eq)

(1.5)

(1.5)
t-BuOK
(1.5)
t-BuOK
(1.5)
t-BuOK
(1.5)

PhSO2Cl
(eq)

18-Crown6

1.5

r.t./42

THF

0: 46

1.5

r.t./41

DMSO

0:40

2+2
49h

0.1

r.t./70

THF

56:28

0.1

r.t./70

Et2O

24:61

0.1

r.t./48

THF

45:14

T (C)/

(h)

121:39
(%)

40

39.
.

t- BuOK
18-Crown-6

N
H
40

SO2Cl

COOEt
THF, RT, 49 h,
2 atm

N
O O2S

COOEt

122

123.
40.
(diethoxymethyl, DEM)

, 36 , 37 38
,
70%.
(140 C)
.
,

-339-

13:

- .
11,
2-
2 , 1-2-- 123 70%.

N
H

COOEt

(EtO)3CH
Reflux, 140h
70%

COOEt

EtO
OEt
123

124. 2
.

, 39
102 ,
71% 9%
.

(EtO)3CH
H3COOC

N
H

COOEt

Reflux, 102h
71%

H3COOC

N
EtO

39

COOEt
OEt

124

125. 39
.
,
34,
.

(EtO)3CH
O

N
H

COOEt

Reflux, 168h

34

N
O
EtO

COOEt
OEt

125

126.
34.

-340-

12:

1980, Guda Marthe7

, , , , ,
,
.
, ,
18---6 ,
.
, ,
-
.

, .

,

39

Guda

Marthe

,
85-90%. (0 C)

18---6.

.

19,

//

1/1.5/3

34, 40, 31 1/1.5/2 39.

1/10 .
,

-341-

13:

5 39 34 ,
40 20 31
15 . ,

(39 40)
,

.
18--6 40 .

,
(aggregated ion pairs),
41
(ligand-seperated ion pairs)
42

18---6 ,

,

,

.
,

.

-342-

12:

19. .

H3COOC
39

N
H
34

N
H

N
H
40

CH3J

(eq)

6 (eq)

(eq)

1.5

0.1

Et2O

r.t.

96

1.5

0.1

Et2O

r.t.

14

88

T (C)

(h)

(%)

COOEt

COOEt

1.5

0.1

Et2O

r.t.

15

81

1.5

0.1

Et2O

r.t.

44

35

59

1.5

0.1

Et2O

r.t.

89

1.5

0.1

Et2O

r.t.

14

87

1.5

0.1

Et2O

r.t.

46

10

85

1.5

0.1

Et2O

r.t.

72

1.5

0.1

Et2O

r.t.

14

10

1.5

0.1

Et2O

r.t.

18

67
15

(%)

COOEt

18-Crown-

t-BuOK

H3COOC
126

1.5

0.1

Et2O

r.t.

20

86

12

1.5

0.1

Et2O

r.t.

21

83

13

1.5

0.1

Et2O

r.t.

24

64

14

1.5

0.1

Et2O

r.t.

30

57

127

N
31 H

N
COOEt
CH3
128

H3COOC

N
COOEt
CH3

N
COOEt
CH3

73

11

COOEt

15

1.5

0.1

Et2O

-343-

r.t.

15

69

H3COOC

N
COOEt
129 CH3

13:

39,

(

20).

80%

. ,

18--

-6 .

H3COOC

t- BuOK
18-Crown-6

N
H

CH2X

H3COOC

COOEt

COOEt

, r.t., 2 atm
130

39

20.
39.

A/A

39
(eq)

(eq)

PhCH2X
(eq)

(eq)

T/

(v/v)

(%)

NaH
(1.2)

PhCH2Cl
(1.2)

r.t./1.75h

DMSO

t-BuOK
(1.5)

PhCH2Cl
(2)

18-Crown-6
(0.1)

r.t./113h

Et2O/THF
(6/1)

t-BuOK
(1.5)

PhCH2Br
(1)

18-Crown-6
(0.1)

r.t./90h

Et2O

Papadopoulos E.P. and Tabello K.I.Y., Alkylation of alkali metal salts

of pyrrole with allyl and propyl tosylate, J. Org. Chem., 1299-1300,
33, 1968.

Jones R.A., The Chemistry of Pyrroles, Academic Press, London,

1977, p. 173

Gonzalez C., Greenhouse R., Tallabs R., Muchowski J., Protecting

groups for the pyrrole nitrogen atom. The 2-chloroethyl, 2phenylsulfonylethyl, and related moieties, Can. J. Chem., 16971702, 61, 1983.

-344-

12:

Heaney H., Ley S.V., N-alkylation of indole and pyrroles in dimethyl

sulphoxide, J. Chem. Soc., Perkin Trans. 1, 499-500, 5, 1973.

Jones R.A. and Candy C.F., Pyrrole studies. XVII. Alkylation of

pyrrylthallium(I), J. Org. Chem., 3993-3994, 36, 1971.

Jonczyk A., Makosza M., Reactions of organic anions. LX. Catalytic

alkylation of some N-H acidic compounds in aqueous medium, Rocz.
Chem., 1203-1205, 49, 1975.

Guida W.C. and Mathre D.J., Phase-transfer alkylation of

heterocycles in the presence of 18-crown-6 and potassium tertbutoxide, J. Org. Chem., 3172-3176, 45, 1980.

Wang N.C., Teo K.E., Anderson H.J., Pyrrole chemistry. XVII.

Alkylation of the pyrrolyl ambident anion, Can. J. Chem., 4112-4116,
55, 1977.

Sukata K., N-Alkylation of pyrrole, indole, and several other nitrogen

heterocycles using potassium hydroxide as a base in the presence of
polyethylene glycols or their dialkyl ethers, Bull. Chem. Soc. Jpn.,
280-284, 56, 1983.

10

Elming N., Clauson-Kaas N., The preparation of pyrroles from

furans, Acta Chem. Scand., 867-874, 6, 1952.

11

Bergauer M., Gmeiner P., Diethoxymethyl protected pyrroles:

Synthesis and regioselective transformations, Synthesis, 2281-2288,
15, 2001.

12

Zelikin A., Shastri V.R., and Langer R., Facile synthesis of 3alkylpyrroles, J. Org. Chem., 3379-3380, 64, 1999.

13

Papadopoules E.P., Haidar N.F., 1-Arenesulfonylpyrroles, Tet. Lett.

1721-1723, 14, 1968.

14

Volker I.O., Phasentransfer-katalysierte N-sulfonierung von indol,

Synthesis, 136, 2, 1979.

15

Xu R., Anderson H.J., Gogan N.J., Loader C.E. and McDonald R.,
Pyrrole chemistry XXV: A simplified synthesis of some 3-substituted
pyrroles, Tet. Lett., 4899-4900, 22, 1981.

16

Kakushima M., Hamel P., Frenette R., and Rokach J., Regioselective
synthesis of acylpyrroles, J. Org. Chem., 3214-3219, 48, 1983.

17

Masaguer C.F., Ravina E., Fueyo J., Alkylation of 3-ethyl-2-methyl4-oxo-4,5,6,7-tetrahydroindole with bromoesters: Benzene sulfonyl
as convenient nitrogen protecting group, Heterocycles, 1303-1309,
34, 1992.

18

Volker I.O., Phasentransfer-katalysierte N-acylierung von indol,

Synthesis, 387-389, 5, 1979.

19

Carpino L.A. and Barr D.E., 7-Azabenzonorbornadiene, J. Org.

Chem., 764-767, 31, 1966.

20

Dhanak D., Neidle S. and Reese C.B., Action of tert-butyl

azidoformate on the conjugate bases of 1,2,3,4-tetrahydro-9Hcarbazole and other indole derivatives, Tet. Lett., 2017-2020, 26,
1985.

-345-

13:

21

Anderson H.J. and Groves J.K., A protecting group for the pyrrole
nitrogen, Tet. Lett., 3165-3166, 34, 1971.

22

Tsuji J., Yuhara M., Minato M., Yamada H., Sato F. and Kobayashi Y.,
Palladium-catalyzed regioselective reactions of silyl-substituted
allylic carbonates and vinyl epoxide, Tet. Lett., 343-346, 29, 1988.

23

Muchowski J.M., and Solas D.R., -substituted pyrroles via

electrophilic substitution of N-triisopropylsilylpyrrole, Tet. Lett.,
3455-3456, 24, 1983.

24

Edwards M.P., Doherty A.M., Ley S.V., and Organ H.M., Preparation
of 2-substituted pyrroles and indoles by regioselective alkylation and
deprotection of 1-(2-trimethylsilylethoxymethyl)pyrrole and 1-(2trimethylsilylethoxymethyl)indole, Tet., 3723-3729, 42, 1986.

25

Dhanak D. and Reese C.B., Studies in the protection of pyrrole and

indole derivatives, J. Chem. Soc., Perkin Trans. 1, 2181-2186, 12
1986.

26

. Saulnier M.G and Gribble G.W., Generation and reactions of 3-lithio1-(phenylsulfonyl)indole, J. Org. Chem., 757-761, 47, 1982.

27

Liu R., Zhang P., Gan T., and Cook J.M., Regiospecific bromination of
3-methylindoles with NBS and its application to the concise synthesis
of optically active unusual tryptophans present in marine cyclic
peptides, J. Org. Chem., 7447-7456, 62, 1997.

28

Soerens D., Sandrin J., Ungemach F., Mokry P., Wu G.S., Yamanaka
E., Hutchins L., DiPierro M., and Cook J.M., Study of the PictetSpengler reaction in aprotic media: Synthesis of the -galactosidase
inhibitor, pyridindolol, J. Org. Chem., 535-5458, 44, 1979.

29

Sundberg R.J. and Russell H.F., Syntheses with N-protected 2lithioindoles, J. Org. Chem., 3324-3330, 38, 1973.

30

Enzo S., Carlo F., Federico P., N-Alkylation of pyrrole and indole
catalyzed by crown ethers, Synthesis, 617-618, 8, 1979.

31

Ottoni O., Cruz R.and Alves R., Efficient and simple methods for the
introduction of the sulfonyl, acyl and alkyl protecting groups on the
nitrogen of indole and its derivatives, Tet., 13915-13928, 54, 1998.

32

Silvestri R., De Martino G., La Regina G., Artico M., Massa S. et al,
Novel indolyl aryl sulfones active against HIV-1 carrying NNRTI
resistance mutations: Synthesis and SAR studies, J. Med. Chem.,
2482-2493, 46, 2003.

33

Rajeswaran W.G. and Cohen L.A., A convenient method of protecting

oxindoles, Tet. Lett., 7813-7814, 38, 1997.

34

Beccalli E.M., Broggini G., Marchesini A. and Rossi E., Intramolecular

Heck reaction of 2- and 3-iodoindole derivatives for the synthesis of
- and carbolinones, Tet., 6673-6678, 58, 2002.

35

Katsunori T., Shin-ichi N., Toshio G., Facile synthesis of 6hydroxyindole and 6-Methoxyindole via regioselective Friedel-Crafts
acylation and Baeyer-Villiger oxidation, Synthesis, 1018-1020, 10,
1994.

-346-

12:

36

Gmeiner P., Bollinger B., Diethoxymethyl: A useful nitrogenprotecting group for lactams and amides, Synthesis, 168-170, 2,
1995.

37

Gmeiner P., Kraxner J., Bollinger B., Diethoxymethyl protected

indoles: Synthesis and regioselective transformations, Synthesis,
1196-1198, 10, 1996.

38

Chery F., Rollin P., De Lucchi O., Cossu S., Phenylsulfonylethylidene

(PSE) acetals: A novel protective group in carbohydrate chemistry,
Synthesis, 2, 286-292, 2001.

39

Mizuno A., Ogata A., Kamei T., Shibata M., Shimamoto T., Hayashi
Y., Nakanishi K., Takiguchi C., Oka N., Inomata N., Synthesis and
serotonin 2 (5-HT2) receptor antagonist activity of 5-aminoalkylsubstituted pyrrolo[3,2-c]azepines and related compounds, Chem.
Pharm. Bull., 623-635, 48, 2000.

40

Gokel W., Durst H.D., Principles and synthetic applications in crown

ether chemistry, Synthesis, 168-184, 3, 1976.

41

Pearson D.E. and Buehler C.A., Potassium

synthesis, Chem. Rev., 45-86, 74, 1974.

42

DiBiase S.A. and Gokel G.W., Crown-cation complex effects. 8.

Reactions of crown ether activated tert-butoxide ion, J. Org. Chem.,
447-452, 43, 1978.

-347-

tert-butoxide

in

14:

14

1-

,
. ,

3-,
2- 1 .
--

2- , 3 2 .
Friedel-Crafts , 3-

2-

.

1--2- , Lewis
4-- ,
Lewis 5 , 4-
. 2- ,
Lewis 5- .
-
- .

-348-

14:

, 1-2-- 120.

, Friedel-Crafts .

Friedel-Crafts,
, 3-
.

1,2-.

21

O
O

O
N
O2S

COOEt

HOOC

N
O2S

COOEt

AlCl3
120

131

ClCH2CH2Cl

21. Friedel-Crafts 120

.

120
(eq)

(eq)

AlCl3
(eq)

T (C)/
(h)

120
(%)

131
(%)

r.t./4.5

87.5

65-75/5

12

45/5.5

86

43/5

89

2--

2,

-349-

14:

(/ 1).
(/ 2)

(1H-NMR,

13

C-NMR, IR).

(/ 3),

.
3-

, 132
9% ( 22, / 1),
(/ 2).

,
,
, (/ 3),
,
4-

(/ 4).

N
O2S
120

COOEt

CH3OCOCH2CH2COCl
AlCl3
ClCH2CH2Cl

-350-

CH3COO

N
O2S
132

COOEt

14:

22. Friedel-Crafts 120

3- .
/

120
(eq)

(eq)

AlCl3
(eq)

T (C)/ (h)

120 (%)

132
(%)

r.t./5

82

40/24

88

10

66

49.75

r.t./21
54/21
65-70/24
r.t./1.75
45/24
65-70/24

Lewis
Friedel-Crafts
- .


.

, Lewis.
Lewis
,
4-.
,
, Lewis ,
.

,
. ,
,

.

120

-351-

14:

.
,

.
5-
,

.

.

1--4-[2-(1,3-)]-4-(2-

-4-) 121,
.
121
133 70%.

30%,

. ,
.

H3COOC

N
O2S

COOEt

H2SO4 30% / CH3COOH

80-100 C, 1:15h
70%

HOOC

N
O2S

121

133

S
(CF3CO)2O
N
O O2S

COOEt

CF3COOH
0 C-RT, 2.5h
30%

134

127. 134.

-352-

COOEt

14:

0 C

134.

38,
.
,
.

DEM-
DEM-

- -
- 4 . DEM

5 .

DEM- Friedel-Crafts

123.

Friedel-Crafts. DEM-
3-

,

1,2-,

135,

2 33%.

-353-

14:

N
EtO

CH3OCOCH2CH2COCl (3eq)
AlCl3 (3eq)

COOEt

H3COOC

ClCH2CH2Cl

OEt
123

N
EtO

0 C, 1.75h
r.t., 1.75h
N2 atm
N
H
2

COOEt

OEt
135

COOEt

128. Friedel-Crafts DEM-

123 3- .
, Lewis



.

1-

-4[2-(1,3-)]-4-(2-4-) 124 ,
Friedel-Crafts. ,
, 30%
DEM- 124

, 38
27%.

H3COOC

N
EtO

COOEt
OEt

H2SO4 30% / CH3COOH

HOOC

r.t, 2h
35 oC, 3.5 h

N
EtO

124

COOEt
OEt

136
S

HOOC

N
H

COOEt

38

129.

124.

-354-

DEM-

14:

,
.

,


.
- .

,

,

.


. ,

--

126

H2SO4 30%
. 137
. ,

128.

-355-

14:

H3COOC

N
COOEt
CH3

H2SO4 30% / CH3COOH

HOOC

65 C, 3h
44%

126
S

N
COOEt
CH3
137

S
(CF3CO)2O
CF3COOH

COOEt
N
CH3

0 C-RT, 2.5h
35%

128

130. 128.

128
40.
,
128,
45%,
38 (44%)
137 (35%). ,

128

96%
H3COOC

N
H

COOEt

H3COOC

N
COOEt
CH3

126

137
35%

95%

44%
HOOC

HOOC

N
COOEt
CH3

39

44%

N
H

COOEt

38

86%

N
H
40

COOEt
O

N
COOEt
CH3
128

131.
128.

-356-

14:

34,

94%
HOOC

N
H

86%

COOEt

N
H

32

COOEt

N
COOEt
CH3
127

34

132. 127
-
129

.
O

H3COOC

N
COOEt
CH3
129

Candy C.F., Jones R.A., Wright P.H., Pyrrole studies. XV. VilsmeierHaack formylation of 1-substituted pyrroles, J. Chem. Soc. [C],
2563-2567, 1970.

Anderson H.J., Griffiths S.J., Pyrrole chemistry. VII. Syntheses and

reactions of some N-substituted pyrroles, Can. J. Chem., 2227-2234,
45, 1967.

Kakushima M., Hamel P., Frenette R., and Rokach J., Regioselective
synthesis of acylpyrroles, J. Org. Chem., 3214-3219, 48, 1983.

Bergauer M., Gmeiner P., Diethoxymethyl protected pyrroles:

Synthesis and regioselective transformations, Synthesis, 2281-2288,
2001.

Bergauer M., Gmeiner P., Traceless linking of pyrroles: general

methology and solid phase supported functionalizations, Synthesis,
274-278, 2002.

-357-

15: -

15

,
, 127 128,

,

,
.

,

/

129,
.
- (128)

128
Fischer.
.

a]

[2,3-

4-

138 .
,
,

-358-

15: -

.
,
.
,
.
7
138. ,
H2SO4 1 .
,

N
COOEt
CH3

N
H

128

S
N
COOEt
CH3

NH

138

N
COOEt
CH3

139

133. 138.

.
, ,

,

.

,

.

128
.

-359-

15: -

.

Fischer.

Beckmann .

.
/ 128
,

S
N
COOEt
CH3

HO

128

N
COOEt
CH3
140

23. 140
A/A

128
(eq)

(eq)

H2NOH
HCl
(eq)

(v/v)

T/

128 (%)

AcONa
(1.5)

1.5

EtOH/H2O
(10/1)

/68h

80

15

Pyridine
(1.5)

1.5

EtOH

/12h

95

anti
. ,
1-NMR

-360-

15: -

. ,
,
0.2 ,

0.2 .


anti
.

Beckmann.
.
,

,
.
, Beckmann

140 40
110 C.
75% ,
.
,
,

Beckmann 1 .

,

,
,

141 142.

-361-

15: -

SOCl2

HO

N
COOEt
CH3

THF

N
COOEt
CH3

140

N
COOEt
CH3

N
H

141

142

24. Beckmann 140

A/A

140
(eq)

SOCl2
(eq)

T/

141/142
(%)

(%)

140
(%)

0/4.5h

85

r.t./6.5h

78

25

14/37

51

25

r.t./7h

29/38

67

25

r.t./9h

35/26

61

25

r.t./15h

38/18

56

0/1
r.t./4.5

5.5h

.

25/1. ,
.

(/ 1, 2).

5.5 15 ,

.


.
141
syn .

-362-

N
O

N
COOEt
CH3

141

15: -

N
COOEt
CH3
OH

HO

syn-

N
COOEt
CH3

anti-

N
H

N
COOEt
CH3

142

134. 140
141 142.

,

.
51-67% Beckmann
.
2



.
O

R'

N
O

N
R

N
O

N
COOEt
CH3

135.
.
(141)
1,3
141.
,
3 ,
,

.
,

-363-

15: -

4 .

-,
,
, , , .

141
, , ,

.


1,3- .

N
H

N
COOEt
CH3

141

N
COOEt
CH3

O
143

25. 1,3-
141.
/

SM
(eq)

(eq)

(v/v)

T /

(%)

Tl(NO3)3.3H20
(2.4)

MeOH/H20
(2.5/1)

0/1h

CuCl2/CuO
(2/4)

Acetone/H2O
(99/1)

r.t./1h

HgCl2/CaCO3
(2.2/2.3)

CH3CN/H2O
(4/1)

r.t./1.25h

TBHP 70%
H20 (2)

Toluene/MeOH
(1/1)

/2.5h

TBHP 70%
H20 (2)

Acetone

/3h

Dess-Martin
Periodinate (2)

CH3CN/CH2Cl2/H2O
(8/1/1)

r.t./1.25h

.
,

-364-

15: -

141

(
25, / 1).

.
6
(/

2)

7,8

(/

3).

(tert-butyl
TBHP) 9 ,

hydroperoxide,

/
(/ 4). , ,
(/ 5).

10

Dess-Martin

(Dess-Martin

11

periodinate, DMP) . DMP 12

141

//
,
.
,
.

1,3-

,
.

144
,
.

-365-

15: -

S X
S
Y

X Y

S X

N
COOEt
CH3

Y
X

S X

H
O
H

N
O

N
COOEt
CH3

N
O

N
COOEt
CH3

N
O

N
COOEt
CH3

N
COOEt
CH3

141

144
-HY
Y
O

X S

-HY
H

N
COOEt
CH3

XSCH2CH2SX
H

O
143

X Y

S X

N
O

S X
S

H
N
COOEt
CH3

OH

N
O

N
COOEt
CH3

=
=

136.
141.

- (128)
1,3-
,

128.
,

.
1,3- ,

.
,

-366-

15: -

. ,
141

N
COOEt
CH3

128

N
COO
Et
CH3
145

26. 1,3-
128.
SM
(eq)

(eq)

(v/v)

T/

(%)

(%)

Dowex 50W
(250mg)
Paraformaldehyde
95% (10)

Acetone/H2O
(99/1)

/48h

70

CH3J (5)

Acetone/H2O
(16/1)

/68h

43

IBX (1.5)

DMSO/H2O
(100/1)

r.t./7h

42

MeOH

/24h

23

DCM

40 C/16h

17

DCM

35 C/17h

14

TBHP 70% H20

(5.8)
(1.933 0h,
1h, 20.75h)
TBHP 70% H20
(6)
TBAB (0.1)
TBHP 5-6 M
(3.3)

13 .

14 ,


. ,

-367-

Dowex

50W

15: -

128,
70%
( 26, / 1).
15 ,
128

43% (/ 2). ,
- (oiodoxybenzoic acid, IBX) 10.
, ,

42%

128

(/

3).

1,3-

TBHP9.

TBHP 0, 1
20.75 128
23% 128
9% 4,7- 146,
(/ 4).


.
O

N
COOEt
CH3

146

TBHP,

,

(/ 5).


. ,

-368-

15: -

128
TBHP

.
.
(/ 6).
TBHP

.
4,7- 146
4,7- 145
, ,

1,3-

128.

, ,

.

-- (129)

128

129.

Fischer.
128

/
. .

-369-

15: -

H3COOC

N
COOEt
CH3
129

H2NOH . HCl (1.5 eq)

CH3COONa (1.5 eq)
CH3CH2OH / H2O
(4.2 / 1)
, 3.5h
92%

OH

H3COOC

N
COOEt
CH3
147

137. 147.

112 113
syn .
Beckmann
147

,

.

OH

H
N

H3COOC

N
COOEt
CH3
147

SOCl2 (25 eq)

THF anh.
r.t., 3h, N2 atm.

H3COOC

N
COOEt
CH3
148

138. Beckmann 147.

Beckmann 147

113.
,

.
149

.

-370-

15: -

Cl
N

H3COOC

S O
H

H
Cl
O S O
N
Cl

Cl

N
COOEt
CH3

H3COOC

N
COOEt
CH3

147

N
-HCl
H3COOC
H

H3COOC

Cl
O S
O

N
COOEt
CH3
O

OH

N
N
COOEt
CH3

H3COOC

N
COOEt
CH3

H3COOC

N
COOEt
CH3
149

148

139.

149

Beckmann 147.


148
127.

- (127)
,
,

.
,
, .

127 3-


3- 127.

.
,

5--4--4,5,6,7-

-371-

15: -

150 16 .

4,5,6,7-

36,

6--7--

3- 37 17 .

Br

X = Br, Cl

N
R
150

Br

N
H

N
H

COOEt
O

36

COOEt

37

140. .

127
3- 151
.

N
H

N
COOEt
CH3

Br
Br3

Pyridine
0 C, 30 min
72%

127

N
COOEt
CH3

O
151

141. 3-- 151.

2-

3 .

N
CH3 O

H
O
O

N
CH3 O

142. 3- 127
.

-372-

15: -

6-.

,
, , -, -, -,
- .

, -
-,

18 ,

-,

Reissert-Henze

(-

19

deficient) - ,
- 20,21 ,

22

- - .

Miyashita 23 ,
, n - . ,
,

,
, -
Grignard .

-
.

--

78 C
. ,

-373-

15: -

78 C,
.

N
COOEt
THF
CH3
-78 oC, Ar atm.

CN

Li

n-BuLi

COOEt
N
CH3

127

TsCN
THF
-78 oC-RT
Ar atm.

N
COOEt
CH3

O
152

143. 3- 127.

,
( ,
50 C,
s )

.

3-
.

Li

Li

N
CH3 O

O
O

N
CH3 O

144. 3-.


127
.
,
3- ,

-374-

15: -

3- -

.
NO2
HNO3
O

N
COOEt
CH3

(CH3CO)2O

127

N
COOEt
CH3

153

24 .
,
127,

3- .

27. 127.
T (C)/
(h)

SM
(eq)

HNO3
(eq)

1.2

-14/1.3
r.t./1.5

0/1.3
r.t./1.5

153
(%)

127
(%)

2.8

37%

41%

2.8

46%

28%

.
(-14 C)
( 27, A/A 1).

.
,
,
.

-375-

15: -

3- 153
(A/A 2).

.


25 .

O
O

O
+ HO N
O

O
O

N
O

-CH3COOH

O
N
CH3 O

O
N

O
O

N
CH3 O

O
O
N
O
O

127

NO2
N
COOEt
CH3

153

H NO
2

-CH3COOH

N
CH3 O

145. 3-
127.

3- 153

-376-

15: -

NHCOR

N
COOEt
CH3

NH2

NO2

N
COOEt
CH3

N N X

N
COOEt
CH3

N
COOEt
CH3

N
COOEt
CH3

R = CN, Cl, Br,

OH, Ph,
H
N

N
CH3 O

146. 3- 153

(127)

-
. -NHCO Schmidt.
,
127 ,

154 (68%).

NaN3 / H2SO4 97%

O

N
COOEt
CH3
127

CH3COOH,
RT 1h, 55 C 2h,
68%

COOEt
N
N
H CH3
154

147. 154.
Schmidt -,
, 26 .
,
80.
1H-NMR
. ,

-377-

15: -

154 ,
,
155 70%.

(CH3CO)2O
Pyridine
N

N
COOEt
CH3

3h, 75 C
70%

154

N
COOEt
CH3

O
155

148. 154.
(127)

,

, , 27,28 .

DDQ 29 ,
(PCC) 30 , Cr3O 31 , t-BuOOH 32 , NaBiO3 33 ,
(CAN) 34 , (IV) 35
36 . ,
, ,

.

- ,
1,3 - 128,

4. ,

.

-378-

15: -

,
.


37 .
t-BuOOH
,
TBAB .
,
0, 45 90
.
4 ,
4,7- 156 4,7- 146 1:1
77%.

t-BuOOH 70%

CuI / TBAB

N
O

COOEt

CH2Cl2, reflux, 4h

CH3

127

N
O

COOEt

N
O

CH3
146

~1 :1

COOEt

CH3
156

(77%)

149.
127.

. ,

.

4,7- 146
.
,
4,7- 4,7 ,

-379-

15: -

Fremy (KSO3)2NO (dipotassium nitrosodisulfonate)]

K2HPO4 38 , CAN 39
() 3 40 . 4,7 , 2,5

41

Hemetsberger-Knittel .

4-7- 159

2,5-

157 158
99% 42 .

OCH3

OCH3
CHO
+

N3

CH3C6H5

O
OCH3

, 5h
99%

158

157

N
H
OCH3

COOEt

159

150. 4,7- 159.

4,7- 146

2,

127
157,
.

N3

O
O 158
+

H3CO

N
H
2

COOEt

N
O

COOEt

OCH3
CHO
N

H3CO

CH3
127

CH3
159

COOEt
OCH3
157

N
O

COOEt

CH3
146

151. 146.

-380-

15: -

4,7-
4,7-

,
(mytomycin C) 43 , discorhabdin A
P388
L1210 44 , wakayin
45,46 .

H
N

O
O

OCONH2
OCH3

H2N
N

H3C

Br
N

N H

O
mitomycin C

N
H

N
H

N
H

discorhabdin

N
H

wakayin

p-
.
Michael ,
,

47,48

R3

O
R1
R2

O
H
N
H

R3

O
R1

R1
H
N
H

R3

R2
O

N
H

R1

R3

R2
O

N
H

R2
O

152. .

Barret Roue 49
4,7-,
5 6

-381-

15: -

4,7-,
(10ml/)
13
2.4/1 75%.
O

N
O

COOEt

CH3
146

NH2
CH3CH2OH / CH3OH
RT, 13h

H
N

N
O

COOEt

N
H

CH3

160

N
O

COOEt

CH3

161

2.4 : 1
(75%)

153. 4,7- 146.

4,7-

-)
6-39,
6-
. ,

5-

4- 5 50 .

Pd-
Pd- -1,4
, murrayaquinone A, purayaquinone A B 51 ,

carbazomycin

H 52

-382-

5H-

15: -

[b]-6,11- 53 , ,
Gram
54,55 .

CH3

CH3

CH3

O
N
H

N
H

purayaquinone A

murrayaquinone A

N
O
H
purayaquinone B

CH3

OR2

CH3
N
HO
H

N
CN

OR1

Kinamycin A R1=Ac, R2=Ac, R3=Ac, R4=Ac

Kinamycin B R1=H, R2=Ac, R3=H, R4=H

Carbazomycin G, R = H,
Carbazomycin H, R = OCH3,

OR3

R4O

(Pd(OAc)2).

,
,
Pd(OAc)2 .
PdII Pd0
.
, Pd(OAc)2

.
,

Heck 56 ,

Pd(OAc)2,
PdII 57
-() -.

, -() . ,
.
Pd0.

-383-

15: -

,
Pd0 PdII.

Pd0, Pd(OAc)2

. , TBHP 58
59 , H2O2, CuCl2, CuNO3 Cu(OAc)2 60 .
1998, Knlker Frhner52,
0.1 Pd(OAc)2
2.5 Cu(OAc)2

carbazomycin G ,
.
Pd0 PdII CuII CuI.

5--4, 7- 160, [3,2b] 162.

, 49
.
73%.

N
N
O
160

CH3

COOEt

Pd(O2CH3C)2

0.1 eq.

Cu(O2CH3C)2

2.5 eq.

CH3COOH, reflux, 30h

73%

N
COOEt
N
O

CH3

162

154. 162.

,
,

, ,

-384-

15: -

. ,
61 .
Pd- 4,7
162.




.
,

[2,3-a],

,

. ,

127

4,7- 160,
,
.

H
N

R
N
H

N
H

COOEt

[2,3-a]

N
H

COOEt

[3,2-b]

Koutsourea A.I., Arsenou E.S., Fousteris M.A, Nikolaropoulos S.S.,

Synthetic approaches for the synthesis of a cytostatic steroidal B-D
bilactam, Steroids, 659-666, 68, 2003.

Cho H., Matsuki S., Mizuno A., Annoura H., Tatsuoka T., Synthesis of
pyrroloazepines. Facile synthesis of 2-substituted pyrrole derivatives
pyrrole derivatives by the phosgene method, J. Heterocyclic Chem.,
87-91, 34, 1997.

Grbel B.-T., Seebach D., Umpolung of the reactivity of carbonyl

compounds through sulfur-containing reagents, Synthesis, 357-402,
1977.

Greene T.W,. Wuts P.G.M, Protective Groups n Organic Synthesis, 3rd

ed., J. Willey & Sons, USA, 1999 p. 337.

-385-

15: -

Jones P.S., Ley S.V., Simpkins N.S. and Whittle A.J., Total synthesis
of the insect antifeedant a jugarin I and degradation studies of
related clerodane diterpenes, Tet., 6519-6534, 42, 1986.

Araki K., Suenaga K., Sengoku T. and Uemura D., Total synthesis of
attenols A and B, Tet., 1983-1995, 58, 2002.

Corey E.J. and Erickson B.W., Oxidative hydrolysis of 1,3-dithiane

derivatives to carbonyl compounds using N-halosuccinimide
reagents, J. Org. Chem., 3553-3560, 36, 1971.

Sabui S.K. and Venkateswaran R.V., Synthesis of O-methyl epiheliannuol E, Tet., 8375-8381, 59, 2003.

Barhate N.B., Shinde P.D., Mahajan V.A. and Wakharkar R.D., A

convenient oxidative demasking of 1,3-dithiolanes and dithianes to
carbonyl compounds with TBHP, Tet. Lett., 6031-6033, 43, 2002.

10

Wu Y., Shen X., Huang J.-H., Tang C.-J., Liu H.-H. and Hu Q.,
Preferential hydrolysis of benzylic/allylic dithianes and dithiolanes
using o-iodoxybenzoic acid (IBX) in DMSO containing traces of
water, Tet. Lett., 6443-6445, 43, 2002.

11

Langille N.F., Dakin L.A., and Panek J.S., A mild, chemoselective

protocol for the removal of thioketals and thioacetals mediated by
Dess-Martin periodinane, Org. Lett., 575-578, 5, 2003.

12

Ireland R.E. and Liu L., An improved procedure for the preparation of
the Dess-Martin periodinane, J. Org. Chem., 2899, 58, 1993.

13

Konwar D., Boruah R.C., Sandhu J.S., An efficient general method

for the deoxygenation of N-arylnitrones, azoxybenzenes, and Nheteroarene N-oxides, Synthesis, 336-337, 1990.

14

Giri V.S., Sankar P. J., Convenient procedure for dethioketalization in

nitrogen heterocycles, Syn. Comm., 1795-1800, 23, 1993.

15

Fetizon M., Jurion M., Aldehydes and ketones from thioacetals, J.

Chem. Soc., Chem. Comm., 382, 1972.

16

Matsumoto M., Ishida Y., Selective halogenation of 4-oxo-4,5,6,7tetrahydroindoles to 5-halo-4-oxo-4,5,6,7-tetrahydroindoles with

copper(II) halides, Heterocycles, 165-170, 23, 1985.

17

Tani M., Ariyasu T., Ohtsuka M., Koga T., Ogawa Y., Yokoyama Y.,
Murakami Y., New strategy for indole synthesis from ethyl pyrrole-2carboxylate (Synthetic studies on indoles and related compounds.
XXXIX), Chem. Pharm. Bull., 55-61, 44, 1996.

18

Kiefel
M.J.,
In:
Comprehensive
Organic
Fuctional
Group
Transformations, ed. Katritzky A.R., Meth-Cohn O. and Rees C.W.
(Eds), Vol. 3, Elsevier Science Ltd, Oxford, New York, Tokyo, 1995, p.
661.

19

Scriven E.F.V.,In: Comprehensive Heterocyclic Chemistry, Katritzky

A.R. and Rees C.W.(Eds), Vol. 2, Pergamon Press, Oxford, 1984, p.
256.

20

Tamura Y., Kawasaki T., Adachi M., Tanio M. and Kita Y.,
Thiocyanation and cyanation using a new combined reagent of

-386-

15: -

triphenylphosphine and thiocyanogen, Tet. Lett., 4417-4420, 50,

1977.
21

Tamura Y., Adachi M., Kawasaki T., Yasuda H. and Kita Y., Cyanation
using the combined reagent, triphenyiphosphinethiocyanogen
(TPPT): A new general route to indole and pyrrole carbonitriles, J. C.
S., Perkin Tans. 1, 1132, 1980.

22

Sakamoto T. and Ohsawa K., Palladium-catalyzed cyanation of aryl

and heteroaryl iodides with copper(I) cyanide, J. Chem. Soc., Perkin
Trans. 1, 2323-2326, 1999.

23

Nagasaki I., Suzuki Y., Iwamoto K.-I., Higashino T., Miyashita

A.,Electrophilic cyanations. II. Synthesis of heteroarenecarbonitriles
by electrophilic cyanation; reaction metalated heteroarenes with ptoluenesulfonyl cyanide, Heterocycles, 443-450, 46, 1997.

24

Morgan K.J., Morrey D.P., Nitropyrroles. I. Preparation

properties of 2- and 3-nitropyrrole, Tet,. 57-62, 22, 1966.

25

Cooksey A.R., Morgan K.J. and Morrey D.P., Nitropyrroles-II. The

nitration of pyrrole, Tet., 5101-5111, 26, 1970.

26

Krow G.R., Nitrogen insertion reactions of bridged bicyclic ketones.

Regioselective lactam formation, Tet., 1283-1307, 37, 1981.

27

Hudlicky M., Oxidations in Organic Chemistry, ACS Monograph 186,

American Chemical Society, Washington DC, 1990.

28

Seldon R.A. and Kochi J.K., Metal-Catalyzed Oxidatons of Organic

Compounds, Academic Press, New York, 1981.

29

Harvey R.G., Pataki J., Cortez C., Di Raddo P., and Yang C.X., A new
general synthesis of polycyclic aromatic compounds based on
enamine chemistry, J. Org. Chem., 1210-1217, 56, 1991.

30

Rathore R., Saxena N., Chandrasekaran S., A convenient method of

benzylic oxidation with pyridinium chlorochromate, Synth. Commun.,
1493-1498, 16, 1986.

31

Wenkert E. and Jackson B.G., Rearrangements and oxidations of

tricarbocyclic diterpenes, J. Am. Chem. Soc., 211-217, 80, 1958.

32

Muzart J., Practical chromiumVI oxide-catalyzed benzylic oxidations

using 70% tert-butylhydroperoxide, Tet. Lett., 2131-2132, 28,
1987.

33

Banik B.K., Venkatraman M.S., Mukhopadhyay C. and Becker F.F.,

Benzylic oxidation by sodium bismuthate in acetic acid: A simple
method for the synthesis of polycyclic aromatic ketones, Tet. Lett.,
7247-7250, 39, 1998.

34

Molander G.A., Application of lanthanide

synthesis, Chem. Rev., 29-68, 92, 1992.

35

Laali K.K., Herbert M., Cushnyr B., Bhatt A. and Terrano D., Benzylic
oxidation of aromatics with cerium(IV) triflate; synthetic scope and
mechanistic insight, J. Chem. Soc., Perkin Trans 1, 578-583, 2001.

36

Nicolaou K.C., Baran P.S., and Zhong Y.-L., Selective oxidation at

carbon adjacent to aromatic systems with IBX, J. Am. Chem. Soc.,
3183-3185, 123, 2001.

-387-

reagents

in

and

organic

15: -

37

Arsenou E.S., Koutsourea A.I, Fousteris M.A., Nikolaropoulos S.S.,

Optimization of the allylic oxidation in the synthesis of 7-keto-5steroidal substrates, Steroids, 407-414, 68, 2003.

38

Kita Y., Tohma H., Inagaki M., Hatanaka K., and Yakura T., Total
synthesis of discorhabdin C: a general aza spiro dienone formation
from O-silylated phenol derivatives using a hypervalent iodine
reagent, J. Am. Chem. Soc., 2175-2180, 114, 1992.

39

Jackson Y.A., Billimoria A.D., Sadanandan E.V., Cava M.P.,

Regioselective Amination of Indole-4,7-quinones, J. Org. Chem.,
3543-3545, 60, 1995.

40

Tapia R.A., Prieto Y., Pautet F., Domard M., Sarciron M.-E.,
Walchshofer N., and Fillion H., Synthesis and antileishmanial activity
of indoloquinones containing a fused benzothiazole ring, Eur. J. Org.
Chem., 4005-4010, 23, 2002.

41

Hemetsberger H., Knittel D., Weidman H., Enazides. I., Synthesis of

ethyl -azidocinnamates, Monatsh. Chem., 1599-1603, 100, 1969.

42

Cherif M., Cotelle P., Catteau J.-P., General synthesis of 2,3substituted 5-membered heterocyclic quinones, Heterocycles, 1749,
34, 1992. Heterocycles, 2349-2362, 34, 1992.

43

Kametani T., Takahashi K., Ihara N., Fukumoto K., Interconversion

between pyrrolo[1,2-a]indoles and 2,3-benzazocin-5-ones -
synthetic approach to mitomycins, Heterocycles, 1371-1375, 6,
1977.

44

Kobayashi J., Cheng J.-F., Ishibashi M., Nakamura H. and Clardy J.,
Prianosin A, a novel antileukemic alkaloid from the okinawan marine
sponge Prianos melanos, Tet. Lett., 4939-4942, 28, 1987.

45

Yan J., Zhong L., and Chen Z., Hypervalent iodine in synthesis. 4.
Oxidative coupling of isopropylidene 5-alkylmalonates using
(diacetoxyiodo)benzene, J. Org. Chem., 459-461, 56, 1991.

46

Kokoshka J.M., Capson T.L., Holden J.A., Ireland C.M., Barrows L.R.,
Differences in the topoisomerase I cleavage complexes formed by
camptothecin and wakayin, a DNA-intercalating marine natural
product, Anti-Cancer Drugs, 758-765, 7, 1996.

47

The Chemistry of the Quinoid Compounds, Saul Patai, (Ed.), John

Wiley & Sons, New York, 1974 pp. 900-916.

48

Cheng J.-F., Nishiyama S., Yamamura S., Synthetic studies on novel

sulfur-containing alkaloids, prianosins isolated from the marine
sponge Prianos melanos. Synthesis of the spirodienone moiety by
phenolic oxidation, Chem. Lett., 1591-1594, 1990.

49

Barret R. and Roue N., Synthesis of a bis-pyrrolo-quinone structure

analogue to wakayin, Tet. Lett., 3889-3890, 40, 1999.

50

Edstrom E.D., Jones Z., Regioselective oxidative amination of 3carbomethoxyindole-4,7-quinones, Tet. Lett., 7039-7042, 36, 1995.

51

Yogo M., Ito C., Furukawa H., Synthesis of some carbazolequinone

alkaloids and their analogs. Facile palladium-assisted intramolecular
ring closure of arylamino-1,4-benzoquinones to carbazole-1,4quinones, Chem. Pharm. Bull., 328-334, 39, 1991.

-388-

15: -

52

Knlker H.-J. and Frhner W., Palladium-catalyzed total synthesis of

the antibiotic carbazole alkaloids carbazomycin G and H, J. Chem.
Soc., Perkin Trans. 1, 173-176, 1998.

53

Bittner S., Krief P., Massil T., Synthesis of carbazoloquinones via

direct palladation of 5-anilino-2-phenylthio-1,4-benzoquinones and of
2-anilino-1,4-naphthoquinones, Synthesis, 215-216, 1991.

54

Furusaki A., Matsui M., Watanabe T., Omura S., Nakagawa A., Hata
T., Crystal and molecular structure of kinamycin C pbromobenzoate, Israel J. Chem., 173-187, 10, 1972.

55

Omura S., Nakagawa A., Yamada H., Hata T., Furusaki A., Watanabe
T., Structures and biological properties of Kinamycin A, B, C, and D,
Chem. Pharm. Bull., 931-940, 21, 1973.

56

Heck R.F., Palladium-catalyzed reactions of organic halides with

olefins, Acc. Chem. Res., 146-151, 12, 1979.

57

Fujiwara Y., Asano R., Moritani I., and Teranishi S., Aromatic
substitution of olefins. XXV. Reactivity of benzene, naphthalene,
ferrocene, and furan toward styrene, and the substituent effect on
the reaction of monosubstituted benzenes with styrene, J. Org.
Chem., 1681-1683, 41, 1976.

58

Aakermark B., Oslob J. D. and Heuschert U., Catalytic oxidative

aromatic cyclizations with palladium, Tet. Lett., 1325-1326, 36,
1995.

59

Aakermark B., Larsson E.M., and Oslob J.D., Allylic carboxylations

and lactonization using benzoquinone and hydrogen peroxide or tertbutyl hydroperoxide as oxidants, J. Org. Chem., 5729-5733, 59,
1994.

60

Knlker H.-J., and O'Sullivan N., Indoloquinones, Part 2 Palladiumpromoted synthesis of a 7-deoxyprekinamycin isomer, Tet. Lett.,
1695-1698, 35, 1994.

61

Knlker H.-J., and O'Sullivan N., Indoloquinones-3. Palladiumpromoted

synthesis
of
hydroxy-substituted
5-cyano-5Hbenzo[b]carbazole-6, 11-diones, Tet., 10893-10908, 50, 1994.

-389-

pro
analysi (Merck, Aldrich, Ferak Riedel de Hen). ,

(Merck Uvasol).
`

(TLC)

TLC (Silica G-25, Macherey-Nagel).

`

0.063-0.2 mm (Silica gel 60F254).
`

80C

.
`

,
Gallenkamp M.p. Apparatus .

.

FT-IR Jasco 5300. 16-64
4000
cm-1 600 cm-1.

,
(KBr)
.

NMR

Bruker

Spectrospin

400

(400

Hz).

(DMSO-d6).

-393-

(CDCl3)

(CHNS Analyzer
Carlo-Erba).

.

HPLC-ESI (AQA Navigator, Finnigan).

-394-

16:

16

2- (2)
2-- (13)
250 ml,
, , 8.25 ml
(73.9 mmol) 12 ml
. 5 ml
(72.1 mmol) 41 ml
1h
.
1h . , 6 g K2CO3 (43.5 mmol)
18 ml
30 min. ,
.
,
. 110
ml .
, , 50 ml
. 13.3 g .
87%
:
.. 74-75 C (. 73-75 C 1 )

2-- (2)
250 ml,
150 ml
1g
.
,

8.63g

(40.6

mmol)

2--

-395-

(13)

16:

, , 10 min.
,

30 min. ,

50 ml 3 130 ml
. ,

. , 50
ml , ,
,
. 5.2 g .
91%
IR (cm-1): 1695, 1180 (-CO-O-), 748 (Ar).
1

H-NMR (CDCl3) (): 9.30 (br s, 1H), 6.88 (dif. t, 1H), 6.85 (dif. t,

1H), 6.19 (dif. q, 1H), 4.25 (q, 2H), 1.29 (t, 3H).

7--4,5,6,7--2-

(34)
4--4-(2--4-) (30)
100 ml 11.2 g (84 mmol)
2.8 g (28 mmol)
20 ml 1,2- .
, 2 g (14.4 mmol) 2--
(2) 20 ml 1,2-
.
2h
. ,
.
,
,
.
/
1:1, 5.8 g .
87%
:

-396-

16:

.. 168 C (. 167-168.5 C 2 )
IR (cm-1): 3365 (OH), 3236 (NH), 1714 (-CO-O-), 1651 (-CH2-CO-C).
1

H-NMR (DMSO-d6) (): 12.50 (br s, 1H), 12.04 (br s, 1H), 7.74 (s,

1H), 6.79 (s, 1H), 4.26 (q, 2H), 3.02 (t, 3H), 2.45-2.53 (t, 3H), 1.28
(t, 3H).

4-(2--4-) (32)
100 ml 4.5 g (19 mmol) 4-4-(2--4-)

(30)

45 ml ,
. , 10.5 ml (66 mmol)

24h . ,

.
,

.


. /
1:1, 3.1 g .
73%
:
.. 86-87 C (. 86-87 C2)
IR (cm-1): 3460 (OH), 3295 (NH), 1705 (-CO-O-), 1675 (-CO-OH).
1

H-NMR (CDCl3) (): 10.99 (br s, 1H), 10.11 (br s, 1H), 6.80 (d, 2H),

4.32 (q, 2H), 2.55 (t, 3H), 2.41 (t, 3H), 1.93 (m, 2H), 1.36 (t, 3H).

7--4,5,6,7--2-

(34)
100 ml 3.1 g (14 mmol) 4(2--4-) (32)
35 ml , .
3 ml (21 mmol)
1h
, . ,

-397-

16:

.
,

,
,

0-30%,

2.7 g .
94%
:
.. 93 C (. 92-93.5 C2)
IR (cm-1): 3267 (NH), 1705 (-CO-O-), 1651(-CH2-CO-C).
1

H-NMR (CDCl3) (): 9.6(s, 1H), 6.65 (s, 1H), 4.29 (q, 2H), 2.69 (t,

3H), 2.48 (t, 3H), 2.07 (m, 2H), 1.30 (t, 3H).

4-(3-)-2-

(31)
100 ml 6.9 g (52 mmol)

3.2

ml

(26

mmol)

3-

20 ml 1,2-

. , 1.8 g (13 mmol)

2-- (2) 20 ml 1,2
.
1h . ,

.
,
, ,
.

-398-

16:

/ 0-3%. 3 g
.
92%
:
.. 113 C (. 113-114 C2)
IR (cm-1): 3277 (NH), 1713 (-CO-O-), 1661 (-CH2-CO-C).
1

H-NMR (DMSO-d6) (): 12.52 (br s, 1H), 7.76 (s, 1H), 7.14 (s, 1H),

4.26 (q, 2H), 3.58 (s, 3H), 3.08 (t, 2H), 2.58 (t, 2H), 1.30 (t, 3H).

4-(3-)-2-

(33)
100 ml 3 g (11.8 mmol)

4-(3-)-2-

(31) 38 ml ,

7.4

ml

(46.2

mmol)

24h
.
,
.
, ,

.

.
o. 2.6g .
91%
:
.. 35 C (. 34.5-35 C2)
IR (cm-1): 3316 (NH), 1705 (-CO-O-Et), 1680 (-CO-Me).
1

H-NMR (CDCl3) (): 10.21(br s, 1H), 6.80 (d, 2H), 4.30 (q, 2H),

3.61(s, 3H), 1.70-2.75 (m, 6H), 1.32 (t, 3H).

4-(2--4-) (32)
10 ml 1 g (4.2 mmol) 4-(3)-2-

-399-

(33)

16:

4 ml 2 ml
30%. 20 min
100 C .
(pH=12)
. ,

37% .

,
. 890 mg .
94%
:
.. 86 C (. 86-87 C2)

4--4-(2-4-) (30).

4--4-(2-

-4-)

4-(3-)-2-

(31)
100 ml 1 g (4.2 mmol)

(30)

4--4-(2--4-)

24

ml

10 95-97%
1h , .
,

3%.
,
,
. 1 g .
96%
:
.. 113 C (. 113-114 C2)

-400-

16:

Friedel-Crafts
2-- (2).

4-(3-)-2-

(35)
100 ml 1g (4.2 mmol)

4--4-(2--4-)

24 ml .
10 95-97%
1h , .


3%.
,
,
. 1.1 g .
98%
: /
.. 94-95 C
IR (cm-1): 3306 (NH), 1714 (-CO-O-), 1671 (-CH2-CO-C).
1

H-NMR (DMSO-d6) (): 12.51(br s, 1H), 7.75 (s, 1H), 7.13 (s, 1H),

4.26 (q, 2H), 4.04 (q, 2H), 3.08 (t, 2H), 2.56 (t, 2H), 1.29 (s, 3H),
1.17(t, 3H).

6--7--4,5,6,7-2- (36)
10 ml 207 mg (1 mmol) 7-4,5,6,7--2- (34)
5 ml ,
. 447 mg CuBr2
1h. ,

celite. .
, ,
,

-401-

16:

.
,

.
/ 0-10%. 254 mg
.
89%
: /
.. 113 C (. 112-113 C2)
IR (cm-1): 3277 (NH), 1703 (-CO-O-), 1663 (-CHBr-CO-C).
1

H-NMR (CDCl3) (): 10.23 (br s, 1H), 6.73 (s, 1H), 4.64 (t, 1H),

4.37 (q, 2H), 2.99-2.93 (m, 1H), 2.77-2.71(m, 1H), 2.49-2.44 (m,
2H), 1.36 (t, 3H).

3--7--4,5,6,7-2- (37)

250 ml 15 ml (186 mmol)
30ml 48% (178 mmol).
8 ml (156
mmol). ,
,
. 100 ml
, 48 g .
96%
:
.. 113 C (. 112-113 C 3, 4 )

3--7--4,5,6,7--2-
(37)
25 ml 500 mg (2.4 mmol) 7-4,5,6,7--2-

(34)

6 ml , .
0 C 771 mg (2.4
mmol)

-402-

16:

6 ml ,

, .
0 C 30min
-.
10%
. , ,
,
.

0-15%.

591

mg

.
86%
: /
.. 127 C (. 126-127.5 C2)
IR (cm-1): 3241 (NH), 1698 (-CO-O-), 1674(-CH2-CO-C).
1

H-NMR (CDCl3) (): 9.77 (br s, 1H), 4.41 (q, 2H), 2.72 (t, 2H), 2.59

(t, 2H), 2.18 (m, 2H), 1.42 (t, 3H).

4-[2-(1,3-)]-7--4,5,6,7--2- (40)
4-[2-(1,3-)]-4-(2--4-) (38)
50 ml 500 mg (2.1 mmol) 4-4-(2--4-)
20 ml

(30)

.
0.32 ml (2.5 mmol) 0.3 ml (3.6
mmol)

1,2-.

9 ,
. , -
.

-403-

16:

0-50%,

656 mg .
99%
: /
.. 156-157 C (. 157-158 C2)
IR (cm-1): 3390 (NH), 3210 (OH), 1705 (-CO-O-).
1

H-NMR (CDCl3) (): 10.71 (br s, 1H), 9.35 (br s, 1H), 7.10 (m,1H),

6.97 (m,1H), 4.32 (q, 2H), 3.40 (s, 4H), 2.61 (m, 4H), 1.37 (t, 3H).
A 4-[2-(1,3-)]-7--4,5,6,7--2 (40)
50 ml 490 mg (1.56 mmol)
4-[2-(1,3-)]-4-(2--4-)
(38) 18 ml ,
. 0 C,
0.59 ml (4.2 mmol)
. ,
, 4 h
. ,
.
,
, ,
.
,
.

0-10%.

204 mg .
44%
: /
.. 150-151 C (. 151-152 C2)
IR (cm-1): 3265 (NH), 1710 (-CO-O-), 1675 (CO).
1

H-NMR (CDCl3) (): 9.61 (br s, 1H), 7.03 (d,1H), 4.35(q, 2H), 3.42-

3.61 (dif., 4H), 2.82-2.65 (dif., 4H), 1.36 (t, 3H).

-404-

16:

4-[2-(1,3-

)]-4-(2--4-)

4-[2-(1,3-)]-4-(2--4) (39)
100 ml 1 g (3.2 mmol)

4-[2-(1,3-)]-4-(2--4-

) (38) 20 ml .
4 95-97%
1h ,
.
,

3%. ,
,
. 1 g .
95%
: /
.. 254 C
IR (cm-1): 3265 (NH), 1710, 1675 (CO).
1

H-NMR (CDCl3) (): 9.84 (br s, 1H), 7.05 (m,1H), 6.92 (m,1H), 4.30

(q, 2H), 3.63 (s, 3H), 3.35 (s, 4H), 2.60-2.44 (m, 4H), 1.36 (t, 3H).

-405-

16:

[2,3-a]

[2,3-a]
(105a-i)
25 ml 207 mg (1 mmol)
7--4,5,6,7--2- (34)
10 ml , ,
. 1.4 mmol
, 164 mg (2 mmol)
100 C
0.75-22 h.
. ,
,
, .

PPSE 5,

6, 7

142 mg (1 mmol) 5 ml
, .
0.34 ml (1.6 mmol)
30 min .
,
, ,
.
5-10 min 180 C.
,
.

(80a-i)

(1 mmol) 100 C

PPSE

(3.5

mmol

) (5 ml) (

-406-

16:

), .

6-8h

,
,
.
,

90:10% 60:40%,
.

4,5--[2,3-a]
(106a-i)

15 ml ,
. 1 mmol 2,3-5,6-
70 C 4-7.5 h . ,


. /

100:0%

80:20%,

-407-

[2,3-a]

28.

16:

[2,3-a] .
5

10

8
9

N
H

N
H

COOEt

IR (cm-1)

H NMR ()

MS

80a

11.40 (s, 1H, NH), 10.44 (s, 1H, NH), 8.17 (d, 1H), 7.91 (d, 1H), 7.63 (d, 1H), 7.55 (d,
1H), 7.47 (t, 1H), 7.43 (s, 1H), 7.33 (t, 1H), 4.53 (q, 2H), 1.55 (t, 3H)

3362, 1672, 1204, 733

277.3

80b

7-CH3

11.67 (s, 1H, NH), 10.61 (s, 1H, NH), 7.76 (s, 1H), 7.66 (d, 1H), 7.45 (d, 1H), 7.27 (d,
1H), 7.18 (s, 1H), 7.07 (d, 1H), 4.27 (q, 2H), 2.36 (s, 3H), 1.26 (t, 3H)

3360, 1667, 1208, 740

291.3

80c

7-CH3O

11.81 (s, 1H, NH), 10.71 (s, 1H, NH), 7.78 (d, 1H), 7.61 (d, 1H), 7.56 (d, 1H), 7.35 (d,
1H), 7.27 (s, 1H), 6.97-6.95 (dd, 1H), 4.36 (q, 2H), 3.83 (s, 3H), 1.35 (t, 3H)

3364, 3335, 1672, 1208, 752

307.4

[M-H]-

80d-1

8-Cl

11.89 (s, 1H, NH), 11.0 (s, 1H, NH), 8.08 (d, 1H), 7.83-7.79 (m, 2H), 7.43 (d, 1H), 7.29
(s, 1H), 7.18 (d, 1H), 4.36 (q, 2H), 1.35 (t, 3H)

3358, 1676, 1206, 737

311.2

80d-2

6-Cl

11.89 (s, 1H, NH), 11.25 (s, 1H, NH), 8.15 (d, 1H), 7.69 (d, 1H), 7.48 (d, 1H), 7.36-7.32
(m, 2H), 7.22 (d, 1H), 4.38 (q, 2H), 1.36 (t, 3H)

3351, 1671, 1208, 727

311.2

80e

9-Cl

11.70 (s, 1H, NH), 11.30 (s, 1H, NH), 8.10 (d, 1H), 7.85 (d, 1H), 7.50-7.46 (m, 2H), 7.34
(s, 1H), 7.22 (t, 1H), 4.40 (q, 2H), 1.39 (t, 3H)

3427, 3288, 1682, 1206, 748

311.2

80f

7-Cl

11.93 (s, 1H, NH), 11.06 (s, 1H, NH), 8.22 (s, 1H), 7.88 (d, 1H), 7.75 (d, 1H), 7.46 (d,
1H), 7.38 (d, 1H), 7.34 (s, 1H), 4.41 (q, 2H), 1.40 (t, 3H)

3350, 1672, 1204, 733

311.2

80g-1

8-Br

11.87 (s, 1H, NH), 10.91 (s, 1H, NH), 8.06-8.01 (m, 2H), 7.82 (d, 1H), 7.45 (d, 1H), 7.337.31 (m, 2H), 4.39 (q, 2H), 1.38 (t, 3H)

3360, 1674, 1206, 754

355.3

80g-2

6-Br

11.85 (s, 1H, NH), 11.18 (s, 1H, NH), 8.33 (d, 1H), 7.77 (d, 1H), 7.50 (d, 1H), 7.41 (d,
1H), 7.34-7.27 (m, 2H), 4.40 (q, 2H), 1.38 (t, 3H)

3360, 1667, 1208, 723

355.3

80h

9-Br

11.73 (s, 1H, NH), 11.20 (s, 1H, NH), 8.14 (d, 1H), 7.85 (d, 1H,), 7.59 (d, 1H), 7.49 (d,
1H), 7.34 (d, 1H), 7.17 (t, 1H), 4.40 (q, 2H), 1.39 (t, 3H);

3430, 3290, 1688, 1206, 750

355.3

80i

7-Br

11.86 (s, 1H, NH), 10.94 (s, 1H, NH), 8.33 (s, 1H), 7.86 (d, 1H), 7.70 (d, 1H,), 7.49-7.43
(m, 2H), 7.32 (d, 1H), 4.39 (q, 2H), 1.38 (t, 3H)

3370, 1674, 1202, 735

355.3

-408-

29.

16:

[2,3-a]

10

8
9

(%)

4
3

(..)

N
H

N
H

COOEt

(oC)

, %

, %

80a

C17H14N2O2 (278.3)

52

302-303

73.37

5.07

10.07

73.53

5.09

10.13

80b

7-CH3

C18H16N2O2 (292.3)

42

311-313

73.95

5.52

9.58

73.85

5.53

9.63

80c

7-CH3O

C18H16N2O3 (308.3)

41

298

70.12

5.23

9.09

70.14

5.25

9.12

80d-1

8-Cl

C17H13ClN2O2 (312.8)

24

327-329

65.29

4.19

8.96

65.49

4.20

8.90

80d-2

6-Cl

C17H13ClN2O2 (312.8)

21

317-318

65.29

4.19

8.96

65.50

4.20

9.02

80e

9-Cl

C17H13ClN2O2 (312.8)

47

285-286

65.29

4.19

8.96

65.42

4.18

8.99

80f

7-Cl

C17H13ClN2O2 (312.8)

39

336-337

65.29

4.19

8.96

65.53

4.18

9.05

80g-1

8-Br

C17H13BrN2O2 (357.2)

23

326-327

57.16

3.67

7.84

57.23

3.66

6.72

80g-2

6-Br

C17H13BrN2O2 (357.2)

20

308-310

57.16

3.67

7.84

57.32

3.68

6.87

80h

9-Br

C17H13BrN2O2 (357.2)

24

305-306

57.16

3.67

7.84

57.26

3.63

7.02

80i

7-Br

C17H13BrN2O2 (357.2)

36

341-342

57.16

3.67

7.84

57.14

3.64

7.08

-409-

16:

3--[2,3-a]

(108a-i)

.

45 min-1.5h.

PPSE
.

(107a-i)

.

.
3h-22h.

3--4,5--[2,3-a ] 109(a-i)

.
4-7.5h.

[2,3-a]

-410-

30.

16:

3--[2,3-a] .
7

4
3

10

N
H

N
H

Br
2

COOEt

IR (cm-1)

H NMR ()

MS

107a

12.17 (s, 1H, NH), 10.85 (s, 1H, NH), 8.15-8.13 (dif., 2H), 7.72 (d, 1H), 7.38 (t, 1H), 7.227.18 (m, 2H), 4.39 (q, 2H), 1.38 (t, 3H)

3356, 1671, 1209, 735

355.3

107b

7-CH3

12.05 (s, 1H, NH), 10.75 (s, 1H, NH), 7.90-7.88 (dif., 2H), 7.59 (d, 1H), 7.26 (d, 1H), 7.21
(d, 1H), 4.42 (q, 2H), 2.47(s, 3H), 1.40 (t, 3H)

3379, 1665, 1204, 735

369.2

107c

7-CH3O

3351, 1667, 1202, 735

385.3

3349, 1667, 1206, 748

389.3

12.08 (s, 1H, NH), 10.70 (s, 1H, NH), 7.93 (d, 1H), 7.68 (s, 1H), 7.63 (d, 1H), 7.26 (d, 1H),
7.02 (dd, 1H), 4.42 (q, 2H), 3.86 (s, 3H), 1.41 (t, 3H)
12.39 (s, 1H, NH), 11.23 (s, 1H, NH), 8.18-8.16 (m, 2H), 7.88 (s, 1H), 7.24-7.18 (m, 2H),
4.40 (q, 2H), 1.39 (t, 3H)

[M-H]-

107d-1

8-Cl

107d-2

6-Cl

12.33 (s, 1H, NH), 11.34 (s, 1H, NH), 8.34 (s, 1H), 7.75 (d, 1H), 7.40 (t, 1H), 7.28 (d, 1H),
7.21 (s, 1H), 4.41 (q, 2H), 1.39 (t, 3H)

3351, 1669, 1208, 729

389.3

107e

9-Cl

12.03 (s, 1H, NH), 11.35 (s, 1H, NH), 8.20-8.16 (m, 2H), 7.50 (d, 1H), 7.26-7.20 (m, 2H),
4.42 (q, 2H), 1.40 (t, 3H)

3430, 3291, 1671, 1211,

743

389.3

107f

7-Cl

12.17 (s, 1H, NH), 11.02 (s, 1H, NH), 8.23 (d, 1H), 7.98 (d, 1H), 7.77 (d, 1H), 7.39 (dd, 1H),
7.32 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H)

3246, 1674, 1211, 750

389.3

107g-1

8-Br

12.35 (s, 1H, NH), 11.16 (s, 1H, NH), 8.24-8.22 (m, 2H), 7.90 (s, 1H), 7.34-7.32 (m, 2H),
4.43 (q, 2H), 1.41 (t, 3H)

3367, 1675, 1208, 743

433.1

107g-2

6-Br

12.27 (s, 1H, NH), 11.26 (s, 1H, NH), 8.52 (s, 1H), 7.80 (d, 1H), 7.45 (d, 1H), 7.34 (t, 1H),
7.21 (s, 1H), 4.42 (q, 2H), 1.39 (t, 3H)

3347, 1671, 1209, 729

433.1

107h

9-Br

12.06 (s, 1H, NH), 11.26 (s, 1H, NH), 8.21-8.18 (m, 2H), 7.63 (d, 1H,), 7.20-7.16 (m, 2H),
4.42 (q, 2H), 1.40 (t, 3H)

3441, 3297, 1674, 1198,

750

433.1

107i

7-Br

12.17 (s, 1H, NH), 11.03 (s, 1H, NH), 8.38 (s, 1H), 7.99 (d, 1H), 7.73 (d, 1H), 7.51 (d, 1H),
7.32 (d, 1H), 4.43 (q, 2H), 1.41 (t, 3H)

3368, 1665, 1206, 795

433.1

-411-

31.

16:

3--[2,3-a] .
7

(%)

4
3

10

(..)

N
H

N
H

Br
2

COOEt

(oC)

, %

, %

107a

C17H13BrN2O2 (357.2)

12

>350

57.16

3.67

7.84

57.21

3.65

7.78

107b

7-CH3

C18H15BrN2O2 (371.2)

10

>350

58.24

4.07

7.55

58.33

4.04

7.51

107c

7-CH3O

C18H15BrN2O3 (387.2)

49

>350

55.83

3.90

7.23

55.87

3.92

7.26

107d-1

8-Cl

C17H12BrClN2O2 (391.6)

22

>350

52.13

3.09

7.15

52.32

3.11

7.08

107d-2

6-Cl

C17H12BrClN2O2 (391.6

16

>350

52.13

3.09

7.15

52.29

3.10

7.16

107e

9-Cl

C17H12BrClN2O2 (391.6)

27

342
(dec)

52.13

3.09

7.15

52.35

3.11

7.19

107f

7-Cl

C17H12BrClN2O2 (391.6)

25

>350

52.13

3.09

7.15

52.22

3.11

7.13

107g-1

8-Br

C17H12Br2N2O2 (436.1)

10

>350

46.82

2.77

6.42

46.89

2.79

6.26

107g-2

6-Br

C17H12Br2N2O2 (436.1)

17

340
(dec)

46.82

2.77

6.42

46.91

2.81

6.37

107h

9-Br

C17H12Br2N2O2 (436.1)

22

>350

46.82

2.77

6.42

46.88

2.80

6.44

107i

7-Br

C17H12Br2N2O2 (436.1)

41

>350

46.82

2.77

6.42

46.94

2.83

6.32

-412-

16:

4-(2-

-4-) (30)

25 ml 239 mg (1 mmol) 4-(2-4-) (30)
12 ml . 350 mg
(5 mmol) , 0.81 ml (10 mmol)
6.5h. ,
,

.

, ,

.
( -
1:120). /
0-3%. 181 mg (110)

H-NMR,

.
71%

25 ml 239 mg (1 mmol) 4-(2-4-) (30)
9 ml . 100 mg
(1.5 mmol) , 123 mg (1.5 mmol)

-413-

16:

, 3 ml
60 C 22h. ,


.
,
,
.
(

1:120)

5-8%.

173 mg (110).
68%

25 ml 239 mg (1 mmol) 4-(2-4-) (30)
9 ml . 100 mg
(1.5 mmol) , 123 mg (1.5 mmol)
, 3 ml , 0.5 ml
60-5 C 7h.


.
,
,

( - 1:120)
/

0-10%.

142 mg (110).
56%

-414-

16:

syn-

4-(3-

-2-

(112)

25 ml 117 mg (1.69
mmol) , 138 mg (1.69 mmol)

7.5

ml

0.5

ml

, 300 mg (1.12 mmol) 4(3-)-2- (35),

6.5 ml .
6h.

.

, ,

( - 1:120)
/ 0-6%.
180 mg (111).
57%

50 ml 418 mg (6
mmol) , 493 mg (6 mmol)
, 29 ml 4 ml . ,

1.07

(4.12

mmol)

)-2-

4-(3(35),

14.5 ml .
3.5h.

.

, ,

-415-

16:

.

. 1.08 g
(112).
91%
:
.. 163-164 C
IR (cm-1): 3353 (OH), 3200 (NH), 1734 (-CO-O-Et), 1674 (-CH2-COO-Et).
1

H-NMR (DMSO-d6) (): 12.09 (br s, 1H), 10.79 (br s, 1H), 7.60

(s,1H), 7.08 (s,1H), 4.15(q, 2H), 3.94 (q, 2H), 2.68 (t, 2H), 2.44 (t,
2H), 1.19(t, 3H), 1.08 (t, 3H).

syn-

4-(3-

-2-

(113)
50 ml 418 mg (6
mmol) , 493 mg (6 mmol)
, 29 ml 4 ml . ,

1.02

(4.03

mmol)

)-2-

4-(3,

14.5 ml .
3.5h.

.

, ,
.

( - 1:120)
/ 0-10%.
950 mg .
88%
:
.. 177-179 C

-416-

16:

IR (cm-1): 3352 (OH), 3182 (NH), 1738 (-CO-O-Et), 1676 (-CH2-COO-Me).

1

H-NMR (DMSO-d6) (): 12.09 (br s, 1H), 10.81 (br s, 1H), 7.60

(s,1H), 7.08 (s,1H), 4.15(q, 2H), 3.49 (s, 3H), 2.69 (t, 2H), 2.44 (t,
2H), 1.19(t, 3H).

4-[2-(1,3-

)]-7--4,5,6,7--2-
(114a 114b)
25 ml 37 mg (0.53
mmol) , 44 mg (0.53 mmol)
, 5 ml 1 ml . ,
105 mg (0.35 mmol) 4-[2-(1,3)]-7--4,5,6,7--2-

5 ml .
4.5h.

.

, ,
.

( - 1:120)
/ 20-50%.
95 mg
86%.
Syn- (114a): 33 mg
30%
:
.. 245-247 C
IR (cm-1): 3345 (OH), 3329 (NH), 1707 (-CO-O-).
1

H-NMR (CDCl3) (): 10.31 (br s, 1H), 9.27 (br s, 1H), 7.02 (d,1H),

4.27(q, 2H), 3.54-3.47 (m, 2H), 3.39-3.32 (m, 2H), 2.73 (t, 2H),
2.41(t, 2H), 1.29(t, 3H).

-417-

16:

Anti- (114b): 62 mg
56%
:
.. 223-225 C
IR (cm-1): 3369 (OH), 3319 (NH), 1680 (-CO-O).
1

H-NMR (CDCl3) (): 10.10 (br s, 1H), 9.52 (br s, 1H), 7.03 (d,1H),

4.27(q, 2H), 3.51-3.44(m, 2H), 3.38-3.31 (m, 2H), 2.96 (t, 2H),
2.37(t, 2H), 1.29(t, 3H).

-418-

16:

--

1--2--

(120)
100 ml 1.68 g (14.38 mmol)
30 ml
30 min, .

. 5 ml
1.33 g (9.57 mmol) 2- (2), 30 ml
. 45 min
. , 3.4 ml (26.26 mmol)

,
. ,
24h
, . ,
,
.
,
,
.
,
.
. 1.74 g
.
65%
: /

-419-

16:

.. 232-233 C
IR (cm-1): 1728, 1177 (-CO-O-), 754, 685 (Ar).
1

H-NMR (CDCl3) (): 7.99 (dif. d, 2H), 7.74 (q, 1H), 7.64 (dif. t, 1H),

7.55 (dif. t, 2H), 7.08 (q, 1H), 6.34 (t, 1H), 4.19 (q, 2H), 1.26 (t,
3H).

1--4-(3-
)-2- (132)
100 ml 240 mg (1.8 mmol)
10 ml 1,2-
. 0.22 ml
(1.8 mmol)

3-

30 min . , 250 mg
(0.9 mmol) 2- 7
ml 1,2-
.
5h
. , -,
.
,
,
.

,

.
205 mg (82%) ,
40 mg .
9%
: /
.. 186-187 C
IR (cm-1): 1730 (-CO-O-Et), 1693 (-CO-).
1

H-NMR (CDCl3) (): 8.32 (dif. d, 1H), 8.04 (dif. d, 2H), 7.68 (dif. t,

1H), 7.58 (dif. t, 2H), 7.42 (dif. d, 1H), 4.21 (q, 2H), 3.72 (s, 3H),
3.17 (t, 2H), 2.77 (t, 2H), 1.28 (t, 3H).

-420-

16:

4-[2-(1,3-)]-4-(1-

-2--4-)
(121)
50 ml 296 mg (0.9 mmol)

4-[2-(1,3-)]-4-(2--4-

(39)

13

ml

, .
0 C, 164 mg (1.35
mmol) 24 mg (0.09 mmol) 18-
-6. 30 min 0 C,

0.23

ml

(1.8
ml

mmol)

0 C 10 min. ,

70h, . 49h 0.23 ml
(1.8 mmol) 2 ml
.

-
.
. ,

,

.
236 mg 82 mg (28%) ,
, .
56%
: /
.. 69-70 C
IR (cm-1): 1742 (-CO-O-Et), 1725 (-CO-O-Me).
1

H-NMR (CDCl3) (): 7.97 (dif. d, 2H), 7.78 (dif. t, 1H), 7.61 (dif. t,

1H), 7.53 (dif. t, 2H), 7.42 (dif. t, 2H), 7.05 (dif. t, 1H),

4.16 (q,

2H), 3.64 (s, 3H), 3.41-3.30 (m, 4H), 2.59-2.51 (m, 4H), 1.23 (t,
3H).

-421-

16:

,
.

4-[2-(1,3-)]-4-(1--2-

-4-) (133)
25 ml 670 mg (1.4 mmol)
4-[2-(1,3-)]-4-(1--2-4-) (121)
9 ml 4.5 ml 30%.
1.25h 80-100 C.
, , pH
12 .
(pH=2)

37%

.
,
.
452 mg .
70%
:
.. 234-236 C
IR (cm-1): 1745 (-CO-O-Et).
1

H-NMR (CDCl3) (): 7.91 (dif. d, 2H), 7.73 (dif. t, 1H), 7.56 (dif. t,

1H), 7.47 (dif. t, 2H), 7.00 (dif. t, 1H), 4.10 (q, 2H), 3.37-3.27 (m,
4H), 2.54-2.47 (m, 4H), 1.18 (t, 3H).

1--4-[2-(1,3-

)]-7--4,5,6,7--2-
(134)
50ml 452 mg 4-[2-(1,3)]-4-(1--2--4) (133) 22 ml
, .
0 C 0.42 ml

-422-

16:

.
2.5h .
,

.
, ,
,
.
,
.
/ 0-5%.
127 mg .
30%
:
.. 255-257 C
IR (cm-1): 1732 (-CO-O-), 1689 (-CH2-CO-).
1

H-NMR (CDCl3) (): 7.56 (d, 2H), 7.69 (t, 1H), 7.61 (t, 2H), 6.94 (s,

1H), 4.43 (q, 2H), 3.58-3.52 (m, 2H), 3.48-3.42 (m, 2H), 2.78 (t,
2H), 2.61 (t, 2H), 1.42 (t, 3H).

--

1- -2--
(123)
50 ml 2 g (14.4 mmol) 2- (2) 24 ml (144 mmol)
.
140h, . ,

(40-65

C)/

05%.

2.43 g .
70%
: 8
IR (cm-1) (film): 1705 (-CO-O-), 1095 (-C-O-C-).

-423-

16:

H-NMR (CDCl3) (): 7.26 (t, 1H), 6.95 (s, 1H), 6.90 (dd, 1H), 6.11

(t, 1H), 4.20 (q, 2H), 3.62-3.57 (m, 2H), 3.52-3.44(m, 2H), 1.27 (t,
3H), 1.17 (t, 6H).

1--4-[2-(1,3-)]-4(2--4-) (124)
25ml 423 mg (1.28 mmol)

4-[2-(1,3-)]-4-(2--4-

) (39) 10ml (60.12 mmol)

.
102h, . ,

,
(40-65 C).
/
2.510% / 10%.
391 g .
71%
:
IR (cm-1): 1735 (-CO-O-Et), 1703 (-CO-O-Me), 1111 (-C-O-C-).
1

H-NMR (CDCl3) (): 7.42 (dd, 1H), 7.00 (dd, 1H), 6.93 (s, 1H), 4.26

(q, 2H), 3.67-3.54 (m, 8H), 3.36 (s, 3H), 2.56-2.50 (m, 4H), 1.37 (t,
3H), 1.22 (t, 6H).

--

1 mmol 5 ml
, , .
0 C . , 182 mg (1.5
mmol) 15
min. 26 mg (0.1 mmol) 18- 6 30 min, 0 C

-424-

16:

0.456

ml

(3

mmol)

4 ml
15 min 0 C
. ,
5-15h,

0-5%.

4-[2-(1,3-)]-4-(1--2-

-4-) (126)
2 eq
.
96%
:
.. 243-245 C
IR (cm-1): 1730 (-CO-O-Et), 1699 (-CO-O-Me).
1

H-NMR (CDCl3) (): 6.95 (dd, 1H), 6.92 (dd, 1H), 4.27 (q, 2H), 3.87

(s, 3H), 3.82 (s, 4H), 2.61-2.48 (m, 4H), 1.35 (t, 3H).

1--7--4,5,6,7--2-

(127)
89%
:
.. 61-62 C
IR (cm-1): 1715 (-CO-O-), 1655 (-C2-CO-C).
1

H-NMR (CDCl3) (): 6.71 (s, 1H), 4.31 (q, 2H), 4.25 (s, 3H), 2.73 (t,

2H), 2.53 (t, 2H), 2.06 (m, 2H), 1.36(t, 3H).

-425-

16:

1--4-[2-(1,3-)]-7--4,5,6,7-

-2- (128)
86%
:
.. 184-185 C
IR (cm-1): 1717 (-CO-O-), 1671 (-C2-CO-C).
1

H-NMR (CDCl3) (): 7.09 (dd, 1H), 4.33 (q, 2H), 4.25 (s, 3H), 3.63-

3.57 (m, 2H), 3.49-3.43 (m, 2H), 2.82 (t, 2H), 2.63 (t, 2H), 1.38(t,
3H).
1--4-(3-)-2 (129)
69%
: /
.. 66-68 C
IR (cm-1): 1735 (-CO-O-Et), 1715 (-CO-O-Me), 1669 (-C2-CO-C).
1

H-NMR (CDCl3) (): 7.52 (s, 1H), 7.25 (s, 1H), 4.33 (q, 2H), 3.91 (s,

3H), 3.69 (s, 3H), 2.83 (t, 2H), 2.62 (t, 2H), 1.35 (t, 3H).

4-[2-(1,3-)]-4-(1--2-

-4-) (137)
25 ml 670 mg (1.95 mmol)

4-[2-(1,3-)]-4-(1--2-

-4-) (126)
9 ml 4.5 ml 30%.
3h 65 C. ,
, pH 12
.
(pH=2)

37%

.
,
.

/ 115%. 280 mg .

-426-

16:

44%
:
.. 233-234 C
IR (cm-1): 3520 (OH), 1705 (-CO-O-).
1

H-NMR (CDCl3) (): 8.62 (br. s, 1H) 6.92 (dd, 1H), 6.89(dd, 1H),

4.24 (q, 2H), 3.84 (s, 3H), 2.52 (br s, 4H), 1.32 (t, 3H)
(137) 1--4-[2-(1,3)]-7--4,5,6,7--2-

(128)
50ml 230 mg (0.7 mmol) 4[2-(1,3-)]-4-(1--2--4) (137) 12 ml
, .
0 C 0.27 ml (1.9 mmol)
.
2.5h
. , -
.
, ,
,
.
,
.
/ 0-5%.
76 mg .
35%

4-[2-(1,3-)]-7--4,5,6,7--2-

-427-

16:

anti-

1--4-[2-(1,3-

)]-7--4,5,6,7--2-
(140)
100 ml 1.09 g (3.5 mmol)
1--4-[2-(1,3-)]-7--4,5,6,7--2 (128) 0.43 ml (5.25
mmol)

40

ml

365 mg (5.25 mmol)

12h .

.
,

. 1.08 g
.
95%
:
.. >330 C (dec)
IR (cm-1): 3426 (OH), 1692 (-CO-O-).
1

H-NMR (CDCl3) (): 7.35 (br. s, 1H) 7.16 (dd, 1H), 4.29 (q, 2H),

4.16 (s, 3H), 3.61-3.54 (m, 2H), 3.45-3.40 (m, 2H), 3.05 (t, 2H),
2.42 (t, 2H), 1.36 (t, 3H).

-428-

16:

Beckmann 1--4-[2(1,3-)]-7--4,5,6,7--2-

25 ml 550 mg (1.68 mmol)

1--4-[2-(1,3-)]-7--4,5,6,7-2- 9.3 ml
, .
0 C, 3.07 ml (42.12 mmol)
20
min.
15h . ,
-, pH 5

25%

.

, ,

,

/ 0-5%.
:

1--4-[2-(1,3-)]-8--4,5,6,7,8-

- [2,3-c]-2- (141):
210 mg
38%
:
.. 176-179 C
IR (cm-1): 3353 (NH), 1701 (-CO-O-), 1616 (--CO-).
1

H-NMR (CDCl3) (): 7.28 (br. s, 1H), 7.23 (br. s, 1H), 4.41-4.29 (dif.

m, 9H), 3.34 (br. s, 4H), 1.42 (t, 3H).

1--4-[2-(1,3-)]-7--4,5,6,7,8- [2,3-b]-2- (142):
100 mg
18%
:
.. 86-88 C

-429-

16:

IR (cm-1): 3344 (NH), 1707 (-CO-O-), 1618 (--CO-).

1

H-NMR (CDCl3) (): 7.33 (br. s, 1H), 7.16 (br. s, 1H), 4.40-4.34 (dif.

m, 9H), 3.04 (t, 2H), 2.73 (t, 2H), 1.42 (t, 3H).
1,3- 1--4[2-(1,3-)]-7--4,5,6,7--2
5 ml 100 mg (0.32 mmol)
1--4-[2-(1,3-)]-7--4,5,6,7--2 2.5 ml .

11

mg

(0.032

mmol)

(TBAB) 0.25 ml (1.93 mmol)

(TBHP) 70%
. 16h 40 C.

,
.
, ,

.
,
. 13 mg 1-4,7--4,7--2- (146).
17%
:
.. 132-134 C
IR (cm-1): 1711 (-CO-O-), 1657 (-CO-).
1

H-NMR (CDCl3) (): 7.31 (s, 1H), 6.65 (dd, 2H), 4.36 (q, 2H), 4.33

(s, 3H), 1.39 (t, 3H).

syn- 1--4-(3)-2- (147)

100 ml 2.13 g (8.0 mmol)
1--4-(3-)-2-
(129) 50 ml
11.8

ml

834

mg

(12

mmol)

, 984 mg

-430-

16:

3.5h.


.
,

. ,

/ 02.5%. 2.08 g .
92%
:
.. 102-103 C
IR (cm-1): 3343 (NH), 1728 (-CO-O-Et), 1709 (-CO-O-Me).
1

H-NMR (CDCl3) (): 8.25 (br. s, 1H) 7.78 (s, 1H), 7.24 (s, 1H), 4.32

(q, 2H), 3.97 (s, 3H), 3.72 (s, 3H), 2.92 (t, 2H), 2.69 (t, 2H), 1.39 (t,
3H).
1--3--7--4,5,6,7-2- (151)
25 ml 2.5 g (11.3 mmol)

1--7--4,5,6,7--2-

(127) 30 ml ,
. 0 C
3.6 g (11.3 mmol)
, 30 ml ,
,
. 0 C
30min -.
10%
. , ,
,
.

-431-

16:

0-5%.

2.45

.
72%
: /
.. 72-73 C
IR (cm-1): 1709 (-CO-O-), 1663 (-C2-CO-C).
1

H-NMR (CDCl3) (): 4.37 (q, 2H), 4.19 (s, 3H), 2.65 (t, 2H), 2.52 (t,

2H), 2.06 (m, 2H), 1.40 (t, 3H).

1--3--7--4,5,6,7-2- (153)
25 ml 111 mg (0.5 mmol)

1--7--4,5,6,7--2-

(127) 4 ml
. 0 C, 0.116 ml (1 mmol)
65 %

2 ml ,

0 C, ,
1h. 1:20h 0 C
1:30h . , ,
.

10%,

, ,
.
,
,
/ 0-15%.
31 mg (28%) ,
61 mg .
46%
: /
.. 70-71 C
IR (cm-1): 1721 (-CO-O-), 1674 (-C2-CO-C), 1495 (NO2), 1350
(NO2).
1

H-NMR (CDCl3) (): 4.47 (q, 2H), 4.00 (s, 3H), 3.07 (t, 2H), 2.58 (t,

2H), 2.14 (m, 2H), 1.39 (t, 3H).

-432-

16:

1--7--4,5,6,7,8-[2,3-b]-2- (154)
25 ml 380 mg (1.72 mmol)
1--7--4,5,6,7--2-

10 ml ,
. 337 mg (5.15 mmol)
2 ml H2SO4 97%
5 min. 1h
2:20h 55 C,
. ,
50 ml 10% pH
7 .

, ,

.
/ 5-15%,
274 mg .
68%
: /
.. 137-138 C
IR (cm-1): 3212 (NH), 1695 (-CO-O-), 1664 (-NH-CO-).
1

H-NMR (CDCl3) (): 8.87 (s, 1H), 6.76 (s, 1H), 4.25 (q, 2H), 3.82 (s,

3H), 2.68 (t, 2H), 2.46 (t, 2H), 2.12 (m, 2H), 1.32 (t, 3H).
8--1--7--4,5,6,7,8-[2,3-b]-2- (155)
10 ml 650 mg (2.75 mmol)
1--7--4,5,6,7,8--[2,3-b]2- (154) 2.5ml
2.5ml .
3h 70 C . ,
,
.
,

-433-

16:

0-6%.

550 mg .
70%
: /
.. 125-126C
IR (cm-1): 1709 (-CO-).
1

H-NMR (CDCl3) (): 6.79 (s, 1H), 4.28 (q, 2H), 3.60 (s, 3H), 2.68 (s,

3H), 2.60-2.56 (m, 2H), 2.34-2.28 (m, 2H), 2.02-1.95 (m, 2H), 1.34
(t, 3H).

-434-

16:

[3,2-b]

1--7--4,5,6,7--2 (127)
10 ml 250 mg (1.13 mmol)

1--7--4,5,6,7--2-

ml

146 mg (0.77 mmol) , 43 mg (0.13

mmol) 1.19 ml (9.43 mmol) P 70%.

4h. 45 90 min
1.19 ml (9.43 mmol) P 70%.
.

5%, 5%,
,
, .

/ 01%.
:

1--4,

7--4,7--2-

(146)
95 mg
36%


1,3- 1--4-[2(1,3-)]-7--4,5,6,7--2-
.

-435-

16:

1--4,7--4,5,6,7--2-

(156),
108 mg
41 %
:
.. 188-191C
IR (cm-1): 1721 (-CO-O-), 1672 (-CH2-CO-C).
1

H-NMR (CDCl3) (): 7.30 (s, 1H), 4.36 (q, 2H), 4.31 (s, 3H), 3.01-

2.92 (m, 4H), 1.38 (t, 3H).

1--4, 7--4,7-2- (146)

50 ml 0.59 ml (6.4 mmol)
13 ml
, . 299 mg (1.28 mmol) 1-4, 7--4,7--2-
30 ml , ,
3h.
13h . ,

.

:
A

1--4,

7--5-(N-)-4,7--2-

(160), 220 mg
53%
: /
.. 211-213C
IR (cm-1): 3235 (NH), 1721 (-CO-O-), 1682 (-NH-C-CO-), 1615 (CH-CO-).
1

H-NMR (CDCl3) (): 7.59 (br. s, 1H), 7.43 (t, 2H), 7.37 (s, 1H),

7.28-7.21 (m, 3H), 6.07 (s, 1H), 4.39-4.33 (m, 5H), 1.41 (t, 3H).

-436-

16:

1--4,7--6-(N-)-4,7--2-

(161),
90 mg
22%
:
.. 242-243 C
IR (cm-1): 3279 (NH), 1711 (-CO-O-), 1672 (-NH-C-CO-), 1617 (CH-CO-).
1

H-NMR (CDCl3) (): 7.48 (br. s, 1H), 7.43 (t, 2H), 7.37 (s, 1H),

7.29-7.20 (m, 3H), 6.11 (s, 1H), 4.43-4.35 (m, 5H), 1.41 (t, 3H).

1--4, 7--5-(N)-4,7--2- (160)

25 ml 254 mg (0.78 mmol)

1--4,

7--5-(N-)-4,7--2-

11.5 ml
. 17.6 mg (0.078 mmol)

() 355 mg () (1.95 mmol).

30 h . ,
,

celite.

0-15%.

184 mg .
73%
: /
.. 296-298C
IR (cm-1): 3275 (NH), 1721 (-CO-O-), 1649 (-CO-).
1

H-NMR (DMSO-d6) (): 12.92 (br. s, 1H), 8.08 (d, 1H), 7.49 (d, 1H),

7.36-7.27 (m, 2H), 7.12 (s, 1H), 4.29-4.23 (m, 5H), 1.29 (t, 3H).

-437-

16:

Bailey D.M., Johnson R.E., Albertson N.F.,

carboxylate, Org. Synt., 100-2, 51, 1971.

Tani M., Ariyasu T., Ohtsuka M., Koga T., Ogawa Y., Yokoyama Y.,
Murakami Y., New strategy for indole synthesis from ethyl pyrrole-2carboxylate (Synthetic studies on indoles and related compounds.
XXXIX), Chem. Pharm. Bull., 55-61, 44, 1996.

Englert S. M. E., McElvain S.M., Bromination of pyridine, J. Am.

Chem. Soc., 863-866, 51, 1929.

Fieser L.F. & Fieser M., Reagents for Organic Synthesis, Vol. 1, Wiley,
New York, 1967, p. 967.

Imamoto T., Yokoyama H., Yokoyama M., Trimethylsilyl

polyphosphate (PPSE). A useful reagent for the Beckmann
rearrangement, Tet. Let., 1803-1804, 22, 1981.

Yamamoto K., Watanabe H., Composition of polyphosphoric acid

trimethylsilyl ester (PPSE) and its use as a condensation reagent,
Chem. Lett., 1225-1228,1982.

Ogata S., Mochizuki A., Kakimoto M., Imai Y., Synthesis of amides
and amidines by reaction of carboxylic acids and amines in the
presence of polyphosphoric acid trimethylsilyl ester (PPSE), Bull.
Chem. Soc. Jpn., 2171-2177, 59, 1986.

Bergauer M., Gmeiner P., Diethoxymethyl protected pyrroles:

Synthesis and regioselective transformations, Synthesis, 2281-2288,
2001.

-438-

Ethyl

pyrrole-2-

155 .
in vitro in vitro

, .
,

N
H

N
H

COOCH2CH3

H3C
N
H

N
H

N
H

COOCH2CH3
Cl

N
H

Cl

N
H

COOCH2CH3

N
H

COOCH2CH3

FM-95-1 ( 80d-1 )

FM-85 ( 80f )

N
H

COOCH2CH3

FM-90 ( 80b )

FM-77 ( 80a )

Cl

N
H

H3CO
N
H

FM-100 ( 80e )

N
H

COOCH2CH3

FM-103 ( 80c )

155.

-441-

in vitro ,

C6

,
CDK1.
in vivo
. ,
in vivo CAM .

(DMSO).
10-2 DMSO

, DMSO
.

.

-442-

[2,3-a]

C6

C6 (TCC),

(GBM),
.

C6

24

20.000 /,
Hams F12 10% (Fetal
Bovine Serum, FBS) . 24
,
, 10-4 8.10-6M.
48 ,
3-[4,5--2-]-2,5-

(3-[4,5-dimethylthiazol-2-yl]-2,5-dimethyl

bromide, MTT) 1 .

-443-

tetrazolium

-6

10

-6

2*10

-6

5*10

-6

8*10

-4

-5

10

10

-10

-20
-30
-40
-50

***
***

-60

***

***
***

FM 77

-5

-6

-4

10

10

10

-10

-20
-30
-40

***

-50

-6

***

FM 90

-60

10

-6

2*10

-6

5*10

-6

8*10

-5

10

-4

10

-10

-20
-30
-40
-50
-60

***

-70
-80

***
FM 100

-444-

***
***

-6

-5

10

-4

10

10

-10
-20
-30

***
***

-40
-50

***
FM 85

-6

10

-6

2*10

-6

5*10

-6

8*10

-5

10

-4

10

-10

-20

**

-30
-40
-50

***

-60

***

***

FM 95-1

-6

10

-6

2*10

-6

-6

5*10

8*10

***

***

-5

***

-4

10

10

***

***

-10

-20
-30
-40
-50
-60
-70

***

FM 103

1.
, FM-77, FM-85, FM-90, FM-95-1, FM-100 FM103 C6
.
%
,
.
(**P < 0.01, ***P < 0.001).

-445-

FM-77, FM-90, FM-95-1, FM-100 FM-103

10-5 10-4M, 10-6M

,
-.
2.10-6M, 5.10-6M 8.10-6M.
FM-77 51%
8.10-6M, 10-5 10-4M
.
FM-85 48%
10-5 M, 10-6 10-4M
.
FM-90, -
50% 10-4M .

FM-95-1,

59%

10-5 M, -
10-6 5.10-6M.
FM-100,
62% 10-5 M , -
10-6 8.10-6M.
, FM-103, 60%
8.10-6 M, -
10-6 8.10-6M.

-446-

[2,3-a]

DNA-

[2,3-a]
,
DNA ,
.
puC18 (125 ng)
37 C
5 ,
. 10-4
10 l.
SDS 0.1%,
, 3,3,55- ( ),
.
0.8% 60V,
1 cm
.
0.1 g/ml TBE
, 2 .

( 2)
FM-77, FM-85, FM-90 FM-95-1

DNA-

DNA,

-447-

77 85

90

90 95
T

T
2.

, FM-77, FM85, FM-90 FM-95-1 DNA- .

-:

DNA- . 77,
85, 90 95: FM-77, FM-85, FM-90 FM-95-1
10-4 .

-448-

[2,3-a]

-
1 (CDK1)

CDK1
MESACUP
MBL (Medical and Biological Laboratories Co., Ltd).

, ,
.
(Enzymed-Linked ImmunoSorbent Assay, ELISA),

.

CDK1

StB,

0.1 g/25 ml.

-3

10

SB

,
, SB1.
7.5 l ,
(ATP)
0.001M. 10-4 .
20

).

(
3)

FM-77, FM-90, FM-95-1 FM-103

-449-

CDK1,
FM-77 . ,
FM-85 , FM-100
.

FM 77

FM 95-1

40

FM 103

FM 90

20
0
-20

FM 85

-40
-60
-80
-100

FM 100

3.
, FM-77, FM-85, FM-90, FM-95-1, FM-100 FM103 10-4 CDK1.
% .

-450-

In

vivo

[2,3-a]

(chorioallantoic

membrane, CAM)
, ,
.
in vivo
,
[2,3-a] .

20 l
1 cm2 CAM,

10-3 .
, 48
37 oC, in situ,
,
. ,

8-10 per data point.

( 4), FM-77, FM-85, FM-90,

FM-95-1, FM-100 FM-103 CAM
. , FM-95-1
.

-451-

10
3
FM

10
0
FM

95
-1
FM

90
FM

85

FM

FM

77

-2
-4

-6
-8
-10

-12
-14

**
*

-16
-18

***

-20

4.
, FM-77, FM-85, FM-90, FM-95-1, FM-100 FM103 in vivo, CAM .
%
.

(*P < 0.05, **P < 0.01, ***P < 0.001).


CAM
, .
CAM
,
. 24 , ,
,

.
,
.

-452-

( 5)
FM-77, FM-85, FM-90 FM-95-1 CAM
. ,

FM-100

FM-103,
.

5.

CAM

, 24
FM-77, FM-85, FM-90 FM-95-1 ( 20 ).
FM-100 FM-103.
1

Papadimitriou E., Heroult M., Courty J., Polycratis A., Stergiou C. and
Catsoris P., Endothelial cell proliferation induced by HARP:
Implication of N or C terminal peptides, Biochem. Bioph. Res.
Commun., 242-248, 274, 2000.

Caceres J.F., Blangy D. and Glikin G.C., Requirement of DNA

topoisomerases for in vitro chromatin assembly by 3T6 mouse cell
extracts, Eur. J. Biochem., 531-537, 181, 1989.

-453-

,
, .

,
, -
,
,

. ,


,
,

,
, ,

-457-

,

.

,
.
,

.
in
vitro

C6

, in vivo

.
1 ,
CDKs,
, , ,
staurosporine , [2,3-d],
, fascaplysin,

-458-

paullones, hymenialdisine .
,

ATP,

.
Flavopiridol 2 , UCN-01 3 Roscovitine 4
.
,

Rebeccamycin,

-DNA,

, - Staurosporine
UCN-01,

,
C.
Arcyriaflavin A
pUL97,
.
,

CDK4/cyclin D1 5 ,

G1

, tjipanazoles
,
topo I.
5,11-dihydroindolo[3,2-b]carbazoles
TCDD, 5, 6, 11, 12tetrahydroindolo[2,3-a]carbazoles .

-459-

.
,

.
,

.

[2,3-a]

34,

2,4-

.
6, 7 ,

Fischer 8 .

9 .

4-

,
,

.
34,
[2,3-a]
.

, ,

Fischer.

Fischer

.
,

[3,3]- .
, ,

-460-

.
,

34

,
,
.

10 .
,
,

,

.

,
PPSE,

.
(one pot reaction),
(105a-i),
( )

PPSE.

, ,

,
.

.
[2,3-a] (80a-i),

(-,

-,

-)

.
,

37 3

-461-

, [2,3a]

(107a-i),

, ,
.

Rebeccamycin

Tjipanazoles.
,

.

,

.



,

.

,
,
,
.
,

.

. ,

(DEM)

.
,
. 1-

-462-

-2-- 120

Friedel-Crafts,

1-

-4[2-(1,3-)]-4-(2--4-)

121

134

39.
,

34 40,
(126) .
,

18-Crown-6

,
. ,

,
.

,
.
128

Fischer.
Beckmann 7- 140

-463-

141 142.
,

1,3-

141
.

(CuCl2/CuO, HgCl2, Tl(NO3)3.3H2),

(TBHP) DessMartin

(DMP),

.
,

128

.

. ,
TBHP 70% ,
4,7- 146.
1,3- ,

127

. ,
(151) 3 (153),

3-

, - 153,
,

,
.

Fischer,
3 .

,

-464-

. , 3-
153

, .
3-

,
Schmidt. 154

4

Fischer .

127.

,
TBHP 70%,
TBAB ,
4,7- 156
4,7- 146 .

4,7-

146

4,7-,

4,7--

,
.
4,7- 146
,
. ,
, ,
5- (160) 6- (161) ,
.
160

-465-

[3,2-b]
162.
,

.


.
,
.

CDKs topo I.
, ,
,

, .
,

. ,

,
.


, Rebeccamycin

topo I 11 . ,

,

, , ,
.
,

12

-466-

,

.

, FriedelCrafts 120,
, ,

.

[2,3-

a]
topo I
CDK1 in vitro, C6
in vitro,
, in vivo.
FM-77, FM-85, FM-90 FM-95-1
topo I
10-4 .
[2,3-a]

,

,
.

FM-77, FM-85, FM-90, FM-95-1, FM-100
FM-103, CDK1/ .
FM-85 FM-100,
CDK1.
FM-85 20%.
FM-100, 100%
.

FM-85, FM-90 FM-103,

-467-

,
- - ,
.
, ,

.
FM-100 ,
FM-85.

ATP.
FM-77, FM-85, FM-90, FM-95-1, FM-100 FM-103

C6

,

, .

-5

48-62% 10

FM-90, , 50%,
10-4 . FM-90, FM-95-1, FM-100
FM-103,
-.
topo I,

topo I. ,
topo I,
/ ,
13, 14 , 15 , 16 .
,


.

EFGR 17

PDGFR 18 ,

19

CDK4 ,
p53, 4a
CDKs p14 p16 20 ,
Ras/MAPK Pi3k/Akt 21 .

-468-

[2,3-a]



.
FM-77, FM-85, FM-90, FM-95-1, FM-100 FM-103

.
, FM-95-1
.

FM100, CDK1/ .


,

VEGF 22 ,

(bFGF)
(matrix metalloproteinases, MMPs) 23 ,

.


CAM,


.

, /

.

,

,

-469-

. ,

,
,

.
[3,2-b]

,
,
,
. ,
, ,
,
.
,


, CDK1
topo I.
,

[2,3-a]

[3,2-b],
.

, ,
,
,
. ,

-470-

,
.

Huwe A., Mazitschek R., Giannis A., Small molecules as inhibitors of

cyclin-dependent kinases, Angew. Chem. Int. Ed., 2122-2138, 42,
2003.

Kim K.S., Sack J.S., Tokarski J.S., et al, Thio- and oxoflavopiridols,
cyclin-dependent kinase 1-selective inhibitors: Synthesis and
biological effects, J. Med. Chem. 4126-4134, 43, 2000.

Akinaga
S.,
Sugiyama
K.,
Akiyama
T.,
UCN-01
(7hydroxystaurosporine) and other indolocarbazole compounds: A new
generation of anti-cancer agents for the new century? AntiCancerDrug Des., 43-52, 15, 2000.

Laurence V., Faivre S., Vera K., Pierga J., Delbaldo C., Bekradda M.,
Armand J., Gianella-Borradori A., Dieras V., Raymond E., Preliminary
results of an ongoing phase I and pharmacokineUc study of CYCE02,
a novel oral cyclin-dependent kinases inhibitor, in patients with
advanced malignancies, Abstract 150, AACR NCI EORTC Mol.Targets
Cancer Ther., 19-22 November, 2002.

Zhu G., Conner S.E., Zhou X., et al, Synthesis, structure-activity

relationship, and biological studies of indolocarbazoles as potent
cyclin D1-CDK4 inhibitors, J. Med. Chem., 2027-2030, 46, 2003.

Brown R.K., In: The Chemistry of Heterocyclic Compounds, Indoles

Part I, Houlihan, W.J (Ed). Wiley-Interscience, John Wiley & Sons,
Inc. New York, 1972, pp. 227-558.

Sundeberg R.J., Comprehensive Heterocyclic Chemistry, Vol 4,

Katritzky A.R., Rees C.W. (Eds), Pergamon Press, Oxford, 1984, pp.
348-376.

Robinson B., The Fischer Indole Synthesis, J. Wiley & Sons, New
York, NY, 1982.

Gribble GW, Recent developments in indole ring synthesis

methodology and applications, J. Chem. Soc., Perkins Trans 1, 10451075, 2000

10

Bergman J., Pelcman B., Synthesis of indolo[2,3-a]pyrrolo[3,4c]carbazoles by double Fischer indolizations, J. Org. Chem., 824828, 54, 1989.

11

Ohkubo M, Nishimura T, Kawamoto H, Nakano M, Honma T, Yoshinari

T, Arakawa H, Suda H, Morishima H, Nishimura S., Synthesis and
biological activities of NB-506 analogues modified at the glucose
group. Bioorg. Med Chem. Lett., 419-422, 10, 2000.

12

Wan Y., Hur W., Cho C.Y., Liu Y., Adrian F.J., Lozach O., Bach S.,
Mayer T., Fabbro D., Meijer L., Gray N.S., Synthesis and target
identification of hymenialdisine analogs, Chem. Biol., 247-259, 11,
2004.

-471-

13

Ciusani E., Perego P., Carenini N., et al., Fas/CD95-mediated

apoptosis in human glioblastoma cells: a target for sensitisation to
topoisomerase I inhibitors. Biochem. Pharmacol., 881-887, 63, 2002

14

Wang Y., Zhu S., Cloughesy T. F., Liau L. M. and Mischel P. S., p53
disruption profoundly alters the response of human glioblastoma cells
to DNA topoisomerase I inhibition, Oncogene, 1283-1290, 23, 2004.

15

Chen T.C., Su S., Fry D., Liebes L., Combination therapy with
irinotecan and protein kinase C inhibitors in malignant glioma.
Cancer, 2363-2373, 97, 2003.

16

Pratesi G.,De Cesare M., Carenini N., Perego P., et al., Pattern of
antitumor activity of a novel camptothecin, ST1481, in a large panel
of human tumor xenografts, Clin Cancer Res. 3904-3909, 8, 2002.

17

Watanabe K, Tachibana O., Sata K., Yonekawa Y., Kleihues P., Ohgaki
H., Overexpression of the EGF receptor and p53 mutations are
mutually exclusive in the evolution of primary and secondary
glioblastomas. Brain Pathol., 217-223, 6, 1996.

18

Hermanson M., Funa K., Koopmann J., Maintz D., et al., Association
of loss of heterozygosity on chromosome 17p with high plateletderived growth factor alpha receptor expression in human malignant
gliomas, Cancer Res., 164-171, 56, 1996.

19

Tremont-Lukats I.W., Gilbert M., Advances in molecular therapies in

patients with brain tumors, Cancer Control, 125-137, 10, 2003.

20

Biernat W., Tohma Y., Yonekawa Y., Kleihues P., Ohgaki H.,
Alterations of cell cycle regulatory genes in primary (de novo) and
secondary glioblastomas, Acta Neuropathol. (Berl), 303-309, 94,
1997.

21

Mischel P.S., Cloughesy T.F., Targeted Molecular Therapy of GBM,

Brain Pathol., 52-61, 13, 2003.

22

Plate KH., Breier G., Weich HA., Risau W., Vascular endothelial
growth factor is a potential tumour angiogenesis factor in human
gliomas in vivo, Nature, 845-848, 359, 1992.

23

Nagase H., Woessner J.F.Jr., Matrix metalloproteinases, J. Biol.

Chem., 21491-21494, 274, 1999.

-472-

.

,
.

(CDKs),
,
,
.


.
,

. ,
CDKs
( / ),
,
ATP
.
, , ,

(fascaplysin),

(paullones)

, (roscovitine),
UCN-01 (flavopiridol)
.

-475-

(rebeccamycin),

(staurosporine)

UCN-01,

(arcyriaflavin A) pUL97
,

CDK4/cyclin D1.

CDKs

,

[2,3-a]
,

,

(key-molecules)

.
[2,3-a]
Fischer 7--

-.

PPSE, ,
,

22 ,
3-
.

-476-

- .


.
,
,
,
.

,
-, -, - . ,
, -

N
COOEt
CH3

127

, 1--7-4,5,6,7--2-

(127)

1--4-[2-(1,3-)]-7--4,5,6,7--

N
COOEt
CH3

-2- (128),

128

HO

, 18---6.
Beckmann 1--4-[2-

140

(1,3-)]-7--4,5,6,7--2-

N
COOEt
CH3

(140), (141, 142).

N
COOEt
CH3

O
141

4- 4--4-(2-4-) (30) 1,3-

(38)

4-[2-(1,3-)]-7--4,5,6,7--2-

(40). ,
1,3-
1--4-[2-(1,3-)]-8--4,5,6,7,8-[2,3-c]-2-

-477-

(141)

N
H
142

N
COOEt
CH3

),
,
. ,

1,3-

1--4-[2-(1,3-

)]-7--4,5,6,7--2-

(128) 4,7-.
1-7--4,5,6,7--2- (127),

.
3-,

Schmidt.
, ,
/

(TBHP),

4,7- (146) 4,7- (156).

5-- (160),

146

N
O

156

N
N
O

b] (162).

COOEt

CH3

, [3,2

COOEt

CH3

N
O

COOEt

CH3

160

[2,3-a],

. ,

O
COOEt

CDKs
, , ,
, ,

.
[2,3-a]
in vitro in vivo
. FM-77(80a), FM-85 (80f), FM-90 (80b)
FM-95-1 (80d-1)
10-4 .
, FM-77, FM-85, FM-90, FM-95-1, FM-100 (80e)
FM-103 (80c),

-478-

N
O
162

CH3

CDK1. , FM-85
20%, FM-100
(100% ).

Cl

N
H

N
H

COOEt

FM-100 ( 80e )

C6

,
48-62% 10-5 ,
FM-90, 50% 10-4 .
FM-90, FM-95-1, FM-100 FM-103
-.
in vivo
(CAM).
, FM-95-1 (80d-1)
. ,
, ,
CAM
.

,

.

- ,
(
)

-479-

[3,2-

b] ,
,


,

-480-

SUMMARY

SUMMARY
The modern strategy of anticancer drug discovery focuses on the
design and synthesis of new therapeutic agents with selective activity
against of particular molecular targets. he intending result of molecular
target inhibition is the improvement of therapeutic effect, the reduction
of undesired side effects and the limitation of the toxicity. Cyclin
dependent kinases (CDKs), enzymes which regulate the transition of the
cell cycle from one phase to another and topoisomerase I, which play
crucial role at DNA replication, are among the molecular targets which
are implicated in the initiation and progression of cancer.
Many research attempts are in progress aiming towards the design
and synthesis of new more efficient CDKs and topoisomerase I
inhibitors. As a result, many new chemical cores have been proved
extremely efficient inhibitors of these enzymes and candidate anticancer
agents. Particularly, the already known CDKs chemical inhibitors
(natural products or/and synthetic molecules) act by competing ATP for
binding in the kinase ATP-binding site, despite their striking chemical
diversity.

Among

indolocarbazole

them

are

analogues,

purine,

heterocyclic

pyrimidine,

flavonoid

and

compounds

(butyrolactone,

fascaplysin, paullones). Some of them like roscovitine, UCN-01 and

flavopiridol are being evaluated for therapeutic use against cancer in
late stages of clinical trials.
Indolocarbazole natural products, like the antibiotic rebeccamycin and
synthetic derivatives, have been proved extremely potent topoisomerase
I

inhibitors,

inhibitory

while

activity

other

indolocarbazole

against

various

derivatives

have

kinases.

Among

protein

shown
them

Staurosporine and its synthetic analogue UCN-01 are non-selective

protein

kinase

cytomegalovirus

inhibitors,
protein

arcyriaflavin

kinase

pUL97,

inhibits

while

the

recently

human
modified

indolocarbazole derivatives have been proved inhibitors of CDK4/cyclin

D1.
According to the above considerations, this thesis was planned and
accomplished based on the structural features and biological activities of
the already known indolocarbazole CDKs and topoisomerase I chemical
inhibitors, as well as the results of structure-activity relationships
studies concerning compounds of this category. A series of pyrrolo[2,3-

-483-

a]carbazole analogues of the aromatic skeleton of the indolocarbazole

natural products was designed and synthesized in order to be evaluated
how this structural modification could contribute in the maintenance, the
enhancement or/and the expansion of biological activity of the basic
indolocarbazole skeleton. Simultaneously, the synthetic methodologies
for the synthesis of the final products were investigated, as well as the
preparation of key molecules which could be used as synthetic
intermediates for the synthesis of modified pyrrolocarbazole analogues.
The synthesis of pyrrolo[2,3-a]carbazole derivatives was achieved
using

Fischer

indole

cyclization

conditions

of

intermediate

arylhydrazones prepared from 7-keto-tetrahydroindolic ketones and

various

arylhydrazines.

However,

the

fragility

and

sensitivity

of

intermediates arylhydrazones guided us to the study and investigation

of proper experimental conditions and catalysts for the synthesis of
product-targets. As a result, the applied general procedure involved the
use of polyphosphoric acid trimethylsilyl ester (PPSE) as a mild aprotic
catalyst for the cyclization step in combination with nitromethane as a
solvent, in one-pot reaction, without isolation of the corresponding
arylhydrazones. 22 final products were synthesized according to this
procedure, eleven of them were unsubstituted at the 3-postion of the
pyrrolocarbazole skeleton and eleven were substituted with a bromine
atom at the same position. The ulterior purpose of the synthesis of
these two series pyrrolocarbazole analogues was the future illation
about the structure-activity relationships concerning compounds of this
category.
In the next step of this thesis the research subject was the chemical
modification of already known intermediate molecules for the synthesis
of

modified

pyrrolocarbazole

derivatives.

To

this

direction,

the

substitution of the pyrrolic nitrogen atom with a proper group, which

would stabilize the pyrrolic ring and would have adequate electronic and
stereochemical features was crucial for the progress of the synthetic
plan.
The attempt to protect intermediate pyrrole or tetrahydroindole
derivatives with various protective groups, such as benzenesulfonyl-,
diethoxymethyl- or benzyl-group proved unsuccessful. This failure in
combination with the undesired removal of the protective group under
the conditions of next synthetic steps, as well as the difficulty of

-484-

introducing particular molecules in the synthetic routes, indicated the

ethyl 1-methyl-7-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (127) and
the

ethyl

1-methyl-4-[2-(1,3-dithiolanyl)]-7-oxo-4,5,6,7-tetrahydro-

indole-2-carboxylate

(128)

as

the

most

appropriate

N
COOEt
CH3

127

synthetic

intermediate molecules. The insertion of the methyl group at the pyrrole

nitrogen atom was achieved according to the application of a modified

N
COOEt
CH3

128

alkylation method of nitrogen heterocyclic compounds under phase

transfer

conditions

in

the

presence

of

potassium

tert-butoxide,

methyliodide and 18-Crown-6.

S

Beckmann rearrangement of the oxime of the ethyl 1-methyl-4-[2(1,3-dithiolanyl)]-7-oxo-4,5,6,7-tetrahydroindole-2-carboxylate

(140)

HO

N
COOEt
CH3

140

afforded the corresponding isomeric lactamic derivatives 141 and 142.

The

protection

of

the

keto-group

of

the

4-keto-4(2S

ethoxycarbonylpyrrol-4-yl)butyric acid (30) with the 1,3-dithiolane

group was necessary for the cyclization of resultant acid (38) to the

N
H

141

dithiolane group from the skeleton of lactam 141 proved unsuccessful,

examined.

Not

only

the

preparation

of

the

N
COOEt
CH3

ester (40). However, all attempts to remove the protective 1,3although ten different, known in the literature, procedures were

N
COOEt
CH3

N
H

corresponding

142

pyrroloazepinodione was unattainable, but also decomposition of the

starting material was the main result. On the other hand, the
deprotection

of

the

ethyl

1-methyl-4-[2-(1,3-dithiolanyl)]-7-oxo-

4,5,6,7-tetrahydroindole-2-carboxylate (128) for the preparation of the

corresponding 4,7-diketone was unsuccessful.
The above results led us to explore the synthetic utilization of ethyl 1methyl-7-oxo-4,5,6,7-tetrahydroindole-2-carboxylate (127) considering
the growing competition for this type of compounds during the last
years. The ester 127 was substituted with a bromine atom or a nitro
group at the 3-position, while the tetrahydroindolic ring was rearranged

N
O

COOEt

CH3
146

to a lactamic one under Schmidt reaction conditions. Also, benzylic type

oxidation

of

the

ester

127

in

two

phase

solvent

system

N
O

COOEt

CH3
156

dichloromethane/water, in the presence of tert-butylhydroperoxide

(TBHP) (70% in water), copper (I) iodide and tetrabutylammnonium
bromide (TBAB), afforded the 4,7-indoloquinone (146) and 4,7-diketone
(156). Then, amination of the double bond of the indoloquinone (146)
and oxidative cyclization of the 5-amino-derivative (160) led to the

N
N
O
160

synthesis of the pyrrolo[3,2-b]carbazoloquinone (162). This new core

-485-

CH3

COOEt

maintains intact the pyrrolic moiety of the pyrrolo[2,3-a]carbazole

analogues, while the carbazolic moiety has been modified with the
insertion of the quinone ring system. However, both skeletons, are flat,
low

molecular

weight,

aromatic

compounds,

with

appropriate

substituents, as the majority of CDKs and topoisomerase I chemical

inhibitors is and can possibly interact with specific parts of these
enzymic complexes causing their inhibition.
Some of the pyrrolo[2,3-a]carbazole analogues were initially tested in
in vitro and in vivo biological assays. The derivatives FM-77(80a), FM-85
(80f), FM-90 (80b) and FM-95-1 (80d-1) inhibited topoisomerase I
activity at final concentration 10-4 M.
The derivatives FM-77, FM-85, FM-90, FM-95-1, FM-100 (80e) and
FM-103

(80c)

were

studied

for

their

CDK1

inhibitory

activity.

Particularly, the derivative FM-85 inhibited enzyme activity 20%, while

the derivative FM-100 caused complete inhibition (100%) of the
enzyme. All the other tested compounds stimulated CDK1 activity.

Cl

N
H

N
H

COOEt

FM-100 ( 80e )

The six aforementioned derivatives inhibited the proliferation of C6

glioblastoma

multiform

cells

in

range

between

48-62%

at

concentration 10-5 M, except for derivative FM-90 which caused an

inhibition at the order of 50% at concentration 10-4 M. The inhibitory
activity of the derivatives FM-90, FM-95-1, FM-100 and FM-103 was
studied in a narrow range of concentrations and it was proved doseresponded. The in vivo chicken embryo chorioallantoic membrane (CAM)
angiogenesis model was used for the determination of the angiogenesis
induction. All the tested compounds caused antiagiogenetic activity,
while the derivative FM-95-1 showed the maximum effect. Finally the
same biological system was used for the toxicity study of the above

-486-

O
COOEt

N
N
O
162

CH3

derivatives. All the tested compounds caused no lesion in treated

compared to untreated tissue (control) and consequently they produced
no toxicity effect.
Results of preliminary biological studies are in accordance with the
initial planning aiming at synthesis of new agents with selectivity against
molecular targets implicated with the initiation and progression of
cancer. It is obvious the necessity for further evaluation of the
pyrrolocarbazole derivatives against related molecular targets. Biological
evaluation of the modified pyrrolocarbazole derivatives and structureactivity relationships, maybe will contribute to the clarification of the
molecular mechanism of action (which is the ulterior scope) and to the
design of analogues with improved biological activities. The pyrrolo[3,2b]carbazoloquinone skeleton with its special molecular features as well
as the key intermediate molecules which are synthesized during the
implementation of the present thesis promote to this direction.
Conclusions of chemical synthesis of intermediate and final products,
as

well

as

conclusions

of

the

biological

evaluation

of

selected

pyrrolocarbazole derivatives can be useful tools for the future design,

application and synthesis of new molecules with all the appropriate
structural characteristics for effective targeting of specific cell cycle
targets.

-487-