Professional Documents
Culture Documents
Luan An Tan
Luan An Tan
1
Tuy nhin, hai hp cht thuc ny cn c nhiu nhc im nh rt nhanh
mt hot tnh do thy phn vng E (vng lacton) ngay c trong mi trng pH
sinh l v gy c vi ty xng [6,8,14,25].
2
Hnh 2: Indotecan (5) v Indimitecan (6)
Trn c s , lun n a ra mc tiu l thit k tng hp cc
indenoisoquinolin mi c nhm th khc nhau vng B khi a thm nhm
hydroxyl vo v tr th 2 ca mch ni propyl cn v tr th 3 l cc d vng
vi hy vng s lm tng kh nng gy c t bo ung th. ng thi lun n
cng thit k tng hp cc indenoisoquinolin mi cha nhm th giu in t
vng B, vi tng lm tng kh nng gy c t bo ung th thng qua
cc lin kt gia indenoisoquinolin vi DNA v Top1 ti v tr phn ct ca
topoisomerase I [22,28,42-45,68].
3
CHNG 1: TNG QUAN
4
1.1.2. Tng hp cc dn cht indenoisoquinolin nh phn ng ngng t
ca anhirit homophtalic vi cc baz Schiff
Mark Cushman v cc cng s nghin cu tng hp cc dn cht ca
indotecan (5) v indimitecan (6) nh m t trong s 1.1.2. Bc cha kha
tng hp khung indenoisoquinolin l phn ng ngng t homophtalic
anhyrit (20) vi baz Schiff (22) nhn c axt 23 chn lc dng cis. Tip
theo, cis axt phn ng vi SOCl2 to thnh clorua axt, sau nh phn ng
axyl ha FriedelCrafts (axyl ha ni phn t) nhn c cht 24. Sau cng
hp cht 24 c phn ng vi cc amin nhn c cc dn cht ca
indotecan (5) v indimitecan (6) [8].
5
nhit phng; (g) SOCl2, nhit phng; (f) imidazol hoc morpholin, NaI, DMF,
70C.
Cng theo phng php ny Gang Ahn v cng s tng hp c
cc dn cht indenoisoquinolin t 31a-31e mt cch d dng nh m t trong
s 1.1.3. Thc t, u tin ca qu trnh tng hp l O-ankyl ha 2, 3 hoc
4hydroxylbenzanehit (26) vi 2-imetylaminoetyl hoc 3-
imetylaminopropyl clorua c cc dn cht hydroxybenzanehit tng ng
27. Tip theo ngng t vi imetylaminoetyl-, propyl- v butylamin c cc
hp cht imin 28, sau cho phn ng vi anhirit homophtalic c hn
hp iastereome ca 3-aryl-4-cacboxylisoquinolon 30. Tip theo, cis axt
phn ng vi SOCl2 to thnh clorua axt, sau nh phn ng axyl ha
FriedelCrafts (axyl ha ni phn t) nhn c cht t 31a-31e [5].
R4
4
a
HO b
3 H 3 H
2 R
2-, 3-, or 4- O R2 O
26 27
hydroxybenzaldehyde
R4 O
c
+
3 O
R
R2 N 29 O
28 R1
4
4 R
HO O R 9
O
d, e 3
3 8 R
R
2 7 2
N R R
R1 N 1
R 31
O 30
O
31a: R1 = (CH2)2-N(CH3)2; R2 = O-(CH2)2-N(CH3)2; R3, R4 = H
31b: R1 = (CH2)3-N(CH3)2; R2 = O-(CH2)2-N(CH3)2; R3, R4 = H
31c: R1 = (CH2)2-N(CH3)2; R2 = O-(CH2)3-N(CH3)2; R3, R4 = H
31d: R1 = (CH2)3-N(CH3)2; R2 = O-(CH2)3-N(CH3)2; R3, R4 = H
31e: R1 = (CH2)4-N(CH3)2; R2, R4 = H; R3 = O-(CH2)2-N(CH3)2
6
Tc nhn v iu kin phn ng s 1.1.3: (a) imetylamino ankyl chlorua Cl-
(CH2)n-N(CH3)2 (n = 2 hoc 3), K2CO3, DMF, un hi lu, 6 h; (b) R1-NH2, MgSO4,
CHCl3,nhit phng,18 h. i vi qu trnh tng hp cc hp cht 28, b sung
TEA; (c) THF (MeOH cho qu trnh tng hp cc hp cht 30e), 0 oC, 1 h; (d)
SOCl2, un hi lu, 18 h; (e) AlCl3, CH2Cl2, 0 oC, 3 h.
Phng php tng hp indenoisoquinolin nh phn ng ngng t ca
anhirit homophtalic vi cc baz Schiff ny cng c Muthukaman
Nagarajan v cc cng s s dng tng hp cc dn cht cha khung
indenoisoquinolin c cha nhm -CHO vng A. i t cht ban u l axt 4-
metylbenzen-1,2-ioic (32) thc hin phn ng vng ha nhm nghin cu
thu c 5-metylanhirit homophtalic (33). Sau cho 33 phn ng vi baz
Schiff 34 thu c hp cht trung gian 35 vi s c mt ca thionyl clorua, s
dng phn ng FriedelCrafts to ra indenoisoquinolin metyl- thay th 36, cui
cng oxi ha 36 c anehit 37 [3].
7
Tc nhn v iu kin phn ng s 1.1.4: (a) AcCl, un hi lu; (b) CHCl3;
(c) (i) SOCl2, PhH, (ii) AlCl3, PhNO2, (ClCH2)2; (d) (i) NBS, AIBN, hv, CCl4, un
hi lu, (ii) AgNO3, ioxan.
Cng theo phng php ny Maris A. Cinelli v cng s tng hp nn
cc indenoisoquinolin c nhm th thay i vng A v vng D. i t
isovanillin (38), Vanillin (45) nhm tc gi thu c cc dn xut
indenoisoquinolin 44a, 44b, 51a, 51b c hot tnh gy c t bo v c ch
topoisomerase I cao [8].
H3CO H3CO
a b
H3CO H3CO O
c
+
N O
BnO H3CO
H O
40 41
OCH3
Br
O
OCH3 OH
CO2H
H3CO
d
H3CO
OBn N Br
H3CO
N Br O
H3CO
43
42
O
OCH3
N
O N 44a
R=
OH
H3CO
O
e
N R N
H3CO R= 44b
O 44
8
nhit phng; (d) (i) SOCl2, nhit phng, (ii) AlCl3 (2 ng lng), 1,2-
icloroetan, nhit phng; (e)imidazol or morpholin, NaI, DMF, 70 C.
BnO BnO
HO
a b
N
H3CO CHO H3CO
H3CO CHO
H
46 47
45
OBn Br
O
OBn
CO 2H OCH3
H3CO H3CO
c OCH3 d
N Br N Br
H3CO H3CO
O O
48 OBn 49 OH
O O
OCH 3 OCH3
H3CO H3CO
f
e
N R N R
H3CO H3CO
O O 51
N N 51a
N 50a R= N
R=
O O
50b N 51b
N R=
R=
9
indenoisoqunolin vi vng D l d t, nh l nit c tm tt trong s
1.1.7 [34].
10
1.1.3. Tng hp cc dn cht indenoisoquinolin da trn phn ng ca
indeno[1,2-c]isochromen-5,11-ion vi cc amin bc 1.
Trc ht tng hp cc indenoisoquinolin theo phng php ny,
Andrew Morrell, Mark Cushman v cng s tin hnh tng hp indeno[1,2-
c]isochromen-5,11-ion nh phn ng ngng t ca 2-cacboxybenzanehit
(56) v phtalit (57) vi s c mt ca NaOMe, MeOH to thnh sn phm
trung gian 58, sau chuyn ha thnh indeno[1,2-c]isochromen-5,11-ion
(59) nh phn ng vng ha trong mi trng axt ch trong mt bc phn
ng nh thit b loi nc DeanStark. Tip , indeno[1,2-c]isochromen-
5,11-ion (59) c chuyn thnh indenoisoquinolin khi phn ng vi amin
bc mt (s 1.1.8) [9].
11
c metyl 5,11-ioxo-5,11-ihydroindeno[1,2-c]isochromen-3-cacboxylat
(63) sau cho 63 phn ng vi amin bc 1 l metyl amin (64) thu c
indenoisoquinolin 65a. Khi thy phn 65a thu c 6-metyl-5,11-ioxo-
6,11-ihydro-5H-indeno-[1,2-c]isoquinolin-3-cacboxylic axt (65b). Hp cht
65b c chuyn i thnh dn xut clorua axt v c x l vi ammoniac
cung cp cc amit tng t 65c (s 1.1.9) [3].
Br
O a b
O
O O
60 O O
O O O 61, 79%
O
OH
O
57
O
O
H3CO O
c
O O
62, 98% 63, 18%
O O
O
H 3C NH2 65a. R= OCH3 ,65%
e
64 65b.R= OH , 76%
f
R N 65c.R= NH2 ,83%
d CH3
O O 65
12
Br OH
a b
O O
O
NC NC
NC
66 O 68 O
67 O
O c
57 O
O O
N
70 R= N
NH2 R
71 R= N O
N R d (e)
O
NC NC 69
72 R= N(CH 3)2
O O
13
Tc nhn v iu kin phn ng s 1.1.11: (a) NH2(CH2)nOH, CHCl3,
nhit phng; (b) N-Boc amino axt, EDCI, DMAP, CH2Cl2, nhit phng, c)
NH2(CH2)2NHBoc, d) HCl, isopropanol, CHCl3, nhit phng, (e) N-Boc amino
axt, EDCI/HOBt hoc HBTU/HOBt, DMAP, CH2Cl2, nhit phng.
Martin Conda-Sheridan v cng s nghin cu tng hp cc dn
xut indenoisoquinolin sunfonat v sunfonamit nh m t trong s 1.1.12
[29].
14
hp cht 83a (R=F, R1= N-metyl-piperazin) c hot tnh v gy c t bo
trn hai dng Hep-G2 v HCT-116 vi gi tr IC50 ln lt l 0,019 v 0,093
M. Ngoi ra, cc cht 83b v 83c c hot tnh gy c t bo trn mt s
dng t bo ung th v hot tnh c ch Top1 tng ng v thm ch cao
hn so vi cc thuc Topotecan (2), Irinotecan (3) (hnh 1.1.1) [6,26].
15
Mark Cushman v cng s nghin cu tng hp cc dn cht
indenoisoquinolin c cha mch nhnh l cc ancol, iol v aminoancol (s
1.1.13, 1.1.14 v 1.1.15) v nghin cu hot tnh gy c trn cc dng t
bo ung th v hot tnh c ch Top1. Trong s cc hp cht tng hp c,
hp cht 87b c hot tnh cao hn so cc thuc camptothecin, cc thuc
Topotecan, Irinotecan (Hai thuc c dn cht thuc lp indenoisoquinolin
ang c th nghim lm sng giai on II) [4].
16
Mark Cushman v cng s s dng phng php ny tng hp cc
bisindenoisoquinolin. Cc hp cht thu c c kh nng c ch
topoisomerase kh tt, hp cht 93h v 93j c kh nng c ch tng ng
Camptothecin (s 1.1.16) [24].
17
l
10 OH
HC
R1
%
18
phn ng oxy ha bi PDC trong metylenclorua thu c cc
indenoisoquinolin 105a-c vi hiu xut rt cao 89-99%.
Won-Jea Cho v cng s tin hnh cc xt nghim th hot tnh gy
c t bo ca cc hp cht tng hp c trn bn dng t bo khi u
ngi bao gm A 549 (khi u phi), Skov-3 (khi u bung trng), SK-MEL-2
(khi u c tnh) v HCT 15 (khi u rut) s dng sunforhodamin B (SRB) xt
nghim. Kt qu cho thy cc dn cht 11-Hydroxyl 100b c khng th
hin kh nng gy c ng k chng li bn dng t bo khi u. Cc hp
cht 104a-c cng khng th hin kh nng gy c mnh. Hp cht 104c cho
thy hiu lc thp (8,9 mol) chng li dng t bo HCT 15. Cc dn cht
11-xeto 105a-c gy c t bo yu (14-30 mol) hoc thm ch hot tnh yu
hn 104a-c. Tuy nhin, s tng cng ng k ca kh nng gy c v hot
tnh c ch Top1 c quan st thy khi cc nhm hydroxyl c
chuyn i thnh cc cht ankoxy tng ng, c bit l cc hp cht 103g-
m. Hp cht isobutoxy 103l hot tnh c ch Top1 mnh nht cng nh kh
nng gy c mnh (1,63-9,92 mol ) chng li c bn dng t bo khi u.
iu th v l cc hp cht 103g - m c cha nhm p-metoxybenzyl cho thy
kh nng gy c t bo mnh hn cc hp cht N-metyl 103a-f [16].
19
sau b oxy ha bi PDC thu c andehit 108a-c vi hiu sut tt (88-
90%). Phn ng ca anehit 108a-c vi Ph3PCH 3Br trong s c mt ca
n-BuLi xy ra cho styren 109a-c vi hiu sut 62-95%. Styren 109a-c x
l vi n-Bu3SnH trong s c mt ca ACCN cho 6,11-ihydro-5H-
indeno[1,2-c]isoquinolin-5-on 110a-c vi hiu sut 55-88%.
PMBO
PMBO
R R1
Me 1) n-BuLi, THF
+ 2) Mel, NaH
N
NC (PMBCl, K2CO3)
R2
NHMe 95 97
94 O
O a: R1 = H, R2 = Me
a: R = H b: R1 = Me, R2 = Me
b: R = Me c: R1 = Me, R2 = PMB
PMBO HO
Br Br H
NBS R1 R1 PDC O
ACCN
DDQ CH2Cl2
CCl4 N N Br
2
hv R H2 O R2 R1
106 CH2Cl2
O 107 O
a: (73%), b: (90%), c: (73%) N
a: (73%), b: (69%), c: (81%) R2
108 O
Me
Br
R1
+
Ph3P CH3Br R1 n-Bu 3SnH
ACCN
n-BuLi, THF N N
R2
Toluen R2
109 110 O
O
20
dy), HT1080 (khi u x) v HL-60 (ung th bch cu). Kt qu c i vi
cc nhm th R1, R2 l cc nhm Me, PMB, H cho thy indenoisoquinolin
110 th hin kh nng gy c chng li nm dng t bo ny mnh hn so
vi 3arylisoquinolin 106, 107, 108 v 109. Hot tnh chng li dng t bo
HL 60 ca indenoisoquinolin 110 trong khong 1,70-8,5 M v dao ng t
2,58 n 9,0 M vi bn dng t bo khc nhng hot tnh c ch Top1 li
khng mnh [17].
Mark Cushman v cc cng s [20] cng s dng phng php ny
tng hp khung indenoisoquinolin thng qua phn ng ng vng ca
(benzo[d][1,3]ioxol-5-yl)(5,8-ihydro-[1,3]ioxolo[4,5-g]isoquinolin-8-
yl)metanol 116 c m t nh s 1.1.19. u tin s to vng bt u
bng vic loi b metanol t hp cht trung gian N-((benzo[d][1,3]ioxol-5-
yl)metyl)-2,2-imetoxyethanamin 111, tip theo l s tn cng ca vng thm
trn cation N-((benzo[d][1,3]ioxol-5-yl)metyl)-2-metoxyethanamin 112. Sau
phn ng thm ha ca vng phenyl dn n hp cht trung gian 5,6,7,8-
tetrahydro-8-metoxy-[1,3]ioxolo[4,5-g]isoquinolin 114. S mt metanol t
hp cht trung gian 114 hnh thnh 1,2-ihydroisoquinolin 115. Bc tip
theo to hp cht trung gian (benzo[d][1,3]ioxol-5-yl)(5,6,7,8-tetrahydro-
[1,3]ioxolo[4,5-g]isoquinolin-8-yl)metanol 116. S tn cng tip theo ca
ion iminium 116 dn n s hnh thnh vng th hai. Qu trnh thm ha
hp cht trung gian 117 thu c dn cht 118, sau do s tch nc v s
tch hiro to norindenoisoquinolin 119 cui cng.
21
S 1.1.19. Tng hp khung indenoisoquinolin thng qua phn ng ng
vng ca (benzo[d][1,3]ioxol-5-yl)(5,8-ihydro-[1,3]ioxolo[4,5-g]
isoquinolin-8-yl)metanol [20].
Hp cht trung gian 116 c th ng phn ha thnh
(benzo[d][1,3]ioxol-5-yl)(5,6-ihydro-[1,3]ioxolo[4,5-g]isoquinolin-8-
yl)metanol 120 v s to vng th hai xy ra trong mi trng axt to hp
cht trung gian 121, sau thm ha cho dn cht 122 v tch hiro hnh
thnh norindenoisoquinolin 119 [20].
22
1.1.5. Tng hp cc dn cht indenoisoquinolin thng qua phn ng ng
vng ca dn cht styrenic enamit.
Cl O
O R3 O R3
2
KHMDS R N P R2 N
THF, -78oC O PhO OPh
O O
R1 -78oC, 20 pht R1 P
126 PhO OPh
127
R4 O
R5 CHO O R3
R 2 xc tc Grubbs' R2 R3
N toluen, un hi luu, 3h N
R5 A B
R4 B(OH)2 76-88%
1 1
128-130 R R
R4
1. Pd(PPh 3)4 5 mol%, OHC D
Na2CO3, H2O 132a-d OHC
2.THF-H 2O, un hi luu, 2h 131a-d R5
72-87%
O O
R2 R3 R2 R3
N PDC, CH2Cl2 N
r.t., 12h
10% HCltrong axeton, R1 R1
C
nhit phng, 24h R4 73-85% R4
81-93% HO 134a-d O
133a-d
R5 R5
R1 R2 R3 R4 R5
a H H Me H H
b H H Me OMe H
c OMe OMe Me H H
d H H Bn H OMe
23
Phn ng tch proton ca 124a, c, d vi NaH trong THF, mui natri amit
NaNH2 v axetylclorua cho dn cht N-axetyl-O-vinylbenzamit 125a, c, d vi
hiu sut 54-66%. Cc hp cht 125a, c, d tip xc vi KHMDS trong THF
-78oC to ra kali enolat 126, sau phn ng vi iphenyl clorophotphat cho
vinyl photphat 127. Tip theo cho dn cht 127 phn ng vi axt 2-
formylboronic 128-130, xc tc Pd(PPh3)4, dung dch Na2CO3 (2M) v mt
vi git EtOH c hi lu trong THF thu c istyren amit 131a-d. Sau
tin hnh phn ng chuyn v ng vng RCM dn cht 131a-d vi 5% mol
cht xc tc Grubbs' th h th 2 trong toluen trong thi gian 3h cho 3-
arylisoquinolon 132a-d vi hiu sut 76-88%. Cc hp cht 132a-d x l vi
10% HCl trong axeton cho cc sn phm ng vng hydroxyl 133a-d vi
hiu sut tt (81-93%). Cui cng nhm hydroxyl ca dn cht 133a-d
chuyn i thnh nhm cacbonyl bi qu trnh oxy ha vi PDC trong
CH2Cl2 cho indenoisoquinolin 134a-d vi hiu sut tt (73-85%) [21,23].
24
1.2. Hot tnh chng ung th ca cc hp cht indenoisoquinolin
1.2.1. C ch c ch topoisomerase I (Top1) ca indenoisoquinolin.
sinh vt nhn chun, topoisomerase I (Top1) l mt enzym cn thit
cho nhiu qu trnh quan trng ca t bo v n gip gin xon DNA si kp
khi DNA thc hin cc qu trnh ti bn v phin m [45-72]. C ch tc
ng ca Top1 bt u vi s tn cng nucleophin ca cc nhm hydroxyl
Tyr723 ca enzym vo mt lin kt phosphoieste trong DNA to thnh mt
phc trung gian trong u 3 ca si gin on c lin kt cng ha tr
vi O-photphoieste v lin kt vi tyrosin ca Top1. Bc tip theo bao gm
mt este c tnh nucleophin tip tc tn cng vo oxy ca hydroxyl ti u 5'
ca si b ph v. Kt thc cc phn ng to ra cu ni photphoieste, hnh
thnh 1 lin kt cng ha tr phc hp: Top1-DNA v cc ngun nng lng
t do. Do hng s cn bng l gn nh nhau v phn ng l t do o
ngc. Tuy nhin, s cn bng c chng minh l c li cho qu trnh ti
xon. Top1-DNA l mt phc trung gian chuyn tip trong phn ng xc tc
ca Top1, gip qu trnh tho xon DNA c tin hnh nhanh chng. Tuy
nhin Top1 cng rt d b mt hot tnh do cc tc ng t mi trng trong
v ngoi t bo, dn n s sai khc, t gy DNA, mt s n v DNA b
oxy ha hoc sa i. Cc tc nhn gy ra s sp xp sai gia cc 5'-
hydroxyl vi cc lin kt photphoieste tyrosyl-DNA lm gin on s to
phc Top1-DNA v c ch cc phn ng ca Top1 [29,42,44].
25
Mt khc, trong t bo lin kt photphoieste c thy phn bng cc
enzym c hiu photpholipaza D nhiu mi trng khc nhau. Trong
Tyrosyl-DNA photphoiesterase I (Tdp1) c chng minh l siu enzym
ch xc tc cho qu trnh thy phn lin kt photphoieste gia Tyr 723 ca
xc tc Top1 v DNA-3'-photphat. Do , Tdp1 c cho l gn vi vic sa
cha cc tn thng DNA. Tdp1 c ph bin sinh vt nhn chun, ng mt
vai tr sinh l quan trng, nh gen t bin H493R chu trch nhim v s
thoi ha him gp ca mt nhim sc th thng gy suy nhc thn kinh -
cn bnh mt iu ha spinocerebellar. Tdp1 cng c kh nng loi b cc 3'-
photphoglycolat do s oxy ha DNA tn thng bi bleomycin v sa cha
li ca phc tch Top 2-DNA. Tt c d kin ny cho thy Tdp1 c mt vai
tr ln trong vic duy tr s n nh ca h gen, c th l thuc chng ung th
hiu qu cao. Nhng nghin cu tinh th hc cho thy Tdp1 gm hai vng
tng tc vi nhau qua mt trc gi 2 ln i xng. Mi vng gp mt gc
histidin (His) v mt gc lysin (Lys) to thnh mt trung tm hot ng
nm trc i xng. Bn gc b sung, N283, Q294, N516 v E538, cng
c sp xp gn v tr hot ng. Cu trc tinh th ca Tdp1 trong phc hp
bc bn ch ra Tdp1 c tng tc vi mt ion vanadat, mt Top1 c ngun
gc t peptide, v mt oligonucleotide DNA si n, t bit c v tr
hot ng ca phc hp ny. Phn na DNA chim 1 vng m hp giu in
tch dng, phn lin kt peptit mt v tr khc hot ng c trng mt
vng m tng i ln c s phn b v in tch. Khi DNA thc hin chc
nng di truyn, DNA- topoisomerase I (top1) tin li gn v tng tc vi
DNA si kp, to phc: Top1-DNA. Kt thc qu trnh, Tpd 1 ct t lin kt
cng ha tr Top1-DNA gii phng enzym Top1, sa cha nhng sai khc
ca DNA [29,49-54].
26
Hnh 1.2.2: M hnh hot ng ca Tdp1 [29].
Khi nghin cu v mt lp th, phn ng xc tc ca Tpd1 c cho l
xy ra theo 2 bc. Bc u tin bao gm s tn cng nucleophin ca gc
His 263 ln nguyn t P lin kt vi nguyn t O trong xc tc Top1 v s tn
cng ca gc Tys723 ti u 3 ca DNA (hnh 1.2.2). Cc nhm chc ca
gc Lys265 v Lys495 c tm thy trong trung tm hot ng ca xc tc l
cc lin kt gia nguyn t O vi nhm photphat, to ra cc lin kt cng
ha tr ca His263 vi u 3-photphat ca DNA. Kt qu l photphoramit
c n nh bng lin kt hiro vi xc tc K265 v K495. bc th 2,
phc trung gian c thy phn bi 1gc His493.H2O thng qua mt phn
ng SN2 th hai. Bc phn ng ny c chng minh nh nghin cu
invitro, cho thy cc t bin SCAN1 H493R dn n s tch ly cc hp cht
trung gian cng ha tr Tdp1-DNA. Sn phm cui cng trong qu trnh ny
27
l mt phn t DNA c u 3'-photphat v gii phng cc gc Hys. Lin kt
photphotyrosyl Top1-DNA c n su bn trong phc hp Top1-DNA v
khng th tip cn vi Tdp1 trc khi phc Top1-DNA bin tnh hoc suy
thoi phn gii protein, Top1 c ngha ln cho hot ng ca enzym Tdp1.
Tdp1 c hiu qu tt trong vic chng li nhiu bin th cu trc ca DNA,
bao gm c si n, si kp di, v si kp gin on, mc d hot ng gim
khi di oligonucleotit c rt ngn. Nhng quan st ny cho thy rng
hot ng enzym ca Tdp1 b nh hng bi di ca chui polypeptit
Top1, ngun gc v cu trc ca cc phn on DNA. Qu trnh ti to li
DNA sau c thc hin bi DNA-polimerase v DNA-ligarase. Vai tr
ca Tpd1 l thy phn lin kt photphotyrosyl-DNA trong phc Top1-DNA
bin tnh hoc thoi ha. iu ny gip nh hng cho qu trnh ha tr liu
l da trn s to thnh nhng tn thng v sai khc trong DNA ca t
bo khi u. Do , phc hp Top1-DNA b mt hot tnh c th pht huy tc
dng ca cc cht gy c Top1 nh camptothecin (CPT) hoc
indenoisoquinolin l cc lp cht c s dng trong iu tr ung th. Nh
vy, cht c ch Tdp1 c th lm tng tc dng ca cht gy c Top1 d s
lin kt gia cc enzym lm cho Tdp1 ch hiu qu cho vic iu tr ung
th t c bit n nh l cc cht c ch. Mc d cc tng tc rng buc
gia Tdp1 v indenoisoquinolin trc y c chng minh bng cng
hng plasmon b mt (SPR) v cng hng hunh quang chuyn tip nng
lng (FRET) nhng cho n nay th c rt t cc cht c ch Tdp1 c bit
n[28-33].
Cc cht c ch Top1 kiu indenoisoquinolin nh Indotecan (5), v
Indimitecan (6), c ch bng cch chn v o ngc lin kt vi b mt phn
cch Top1-DNA. Hot ng c ch Tdp1 c o bng kh nng ca thuc c
ch qu trnh thy phn cc lin kt photphodieste gia tyrosin v 3'-cui ca
b mt DNA ngn chn s to ra mt oligonucleotit vi mt u 3'-
28
photphat t do. Cc khu vc khc nhau ca phn t indenoisoquinolin c
ti u ha cho hot ng c ch Top1 bao gm s gn d vng nit vo vng
lactam, nitrat ha trong vng isoquinolin, chiu di ca lactam ph chui v
nhm th trong 9 v tr th [28,42, 44, 68-72]. Cc hp cht c tc dng c ch
Top1, Tdp1 nh Camptothecin, Indenoisoqiunolin c kh nng xen vo gia
cu trc cc cp baz ca DNA trong phc ti 2 v tr. Cc hp cht ny lin
kt cng ha tr phc hp vi Top1-DNA v c ch s ti to mt si n m
enzym to ra lm gim sc cng trong DNA siu xon. Cc nh khoa hc
tin hnh tm hiu v nghin cu cu trc tinh th bng X-ray ca phc
Top1-DNA khi tng tc vi mt s cc cht i din ca indenoisoquinolin
cng nh cc nhm cht Camptothecin, indolocarbazol (cc cht gy c
Top1) v a ra m hnh phc hp indenoisoquinolin-Top1-DNA nh hnh
1.2.3.
29
Tnh cht phng ca cc lp cu trc a dng cho php chng bt chc
mt cp baz DNA xen gia cc cp baz c s DNA hnh thnh tng tc
xp chng v c hai pha trn v di cp baz ti v tr ca s phn ct si.
Tt c cc hp cht c mt cp electron t do gn Arg364 (1 gc c th t
bin khng i vi c ba loi thuc: Camptothecin, indenoisoquinolin,
indolocarbazol). Kiu tng tc chung ca c 3 nhm cht u c thc hin
nh lin kt trc tip vi cc gc axt amin Asn352 v Glu356. Cc cu trc
X-ray mi gii thch cch cc phn t rt khc nhau c th n nh khu phc
hp lin kt cng ha tr Top1-DNA v h tr thit k hp l cc lp cu trc
hon ton mi ca thuc chng ung th. Cc m hnh cu trc ny cho thy
cc mi quan h cu trc hot ng gia cc indenoisoquinolin. Kt qu cho
thy Indenoisoquinolin c kiu tng tc xen k v bt chc mt cp baz
DNA ti v tr ca Top1 qua trung gian phn chia, tip xc vi c DNA v
protein [22,42,45,68,72].
30
xen vo ti v tr ca s phn ct DNA, gia cc cp c s +1 v -1. Vng C v
D vi cc si khng phn chia, trong khi vng A v B chm vi cc si
scissile. Vng C-cacbonyl l pha bn rnh nh ca vng indenoisoquinolin
v tng tc vi hai nit ca chui bn Arg364 khong cch 2,8 v 3,0 .
Nhm th axt butyric trn nit vng B trong rnh ln i vi Asn352 v
Ala351. Phn tch v mi quan h cu trc hot ng ca indenoisoquinolin so
snh vi cu trc tinh th MJ238 c th a ra mt s khi qut lin quan n
indenoisoquinolin. u tin, vng C v D xen DNA bng cch xp chng trn
si nguyn vn ca ADN tng t nh v tr cc vng A v B ca
Camptothecin. Th hai, hu ht cc hp cht indenoisoquinolin cha mt cp
electron gi nh t do thc hin mt lin kt hydro vi Arg364 n nh
tng tc protein- thuc. Th ba, nhm th trn nguyn t nit N6 c d
on s vo rnh chnh Asn352. Cc nhm th butanoic ca indenoisoquinolin
MJ238 i vo trong khoang rnh ln hng v pha u cui ca DNA. Cc
dn xut indenoisoquinolin vi hydroxyankyl hoc mch nhnh ankylhalogen
gy c t bo nhiu hn so vi khng c mch nhnh ti nit N6
[28,31,44,63,68].
31
Cc indenoisoquinolin ang c nghin cu pht trin bng cch sng
lc cc c s d liu thuc thuc chng trnh pht trin nghin cu ca vin
ung th quc gia M cho cc hp cht gy c t bo c cu hnh lin quan
vi camptothecin trn 60 dng t bo ung th khc nhau. Cc nh khoa hc s
dng gi tr gy c t bo GI50 l nng tng ng vi s c ch tng
trng ln n 50%. MGM (Mean Graph Midpoint) l cc gi tr trung bnh
da trn tnh ton theo phng php th ca gi tr GI50 trung bnh cho tt
c cc dng t bo th nghim (khong 60 dng) trong gi tr GI50 cho
nm trong phm vi cho php l 10-8M - 10 -4M (10-8 v 10 -4 ln lt l nng
ti thiu v ti a ca thuc trong qu trnh xt nghim kim tra). Mt hp
cht c xem l hot ng nu n c gi tr MGM 1M v c kh nng
c ch Top1 ngang bng hoc hn hot tnh ca Camptothecin. Kh nng c
ch Top1 so vi Camptothecin c th hin: 0/+ khng pht hin c hot
tnh, ++ hot ng yu, +++ hot ng tng t camptothecin, ++++ v
+++++ hot ng mnh hn rt nhiu so vi camptothecin [8,22,68].
O O OCH3
O O O
O O
H3CO H3CO
N O N N N NH2
N H3CO N O2N
H3CO
O O
O
Indimitecan (6) 135
Indotecan (5) Top 1: +++++
Top 1: +++++
Top 1: +++++ TDP1: +++
MGM: 0,079 M
MGM: 4,64 M MGM: 0,027 M
OH
OH O
O
O
OCH3
OCH3 H3CO OCH
H3CO 3
N NH2
N N O2N
N N O H3CO N
H3CO O
O
O
51a 136
51b Top 1: +++++(+) Top 1: ++++
Top 1: +++++ MGM: 0,055 M TDP1: +++
MGM: 0,087 M MGM: 1,41 M
32
1.2.2. Hot tnh chng ung th ca cc dn xut indenoisoquinolin c
nhm aminopropyl vng B.
Cc mnh nhnh aminopropyl c vai tr quan trng quyt nh hot tnh
ca enzym c ch nh quan st thy 137b: +; 138: ++(+); 139: ++ 140: ++++;
141: ++++ ; 142: ++++.
33
Hnh 1.2.8: M hnh lin kt gi ca 138 trong trung tm hot ng ca Tdp1
[28].
Cc nhm N-(3-aminopropyl) ca indenoisoquinolin 138 c th ng
mt vai tr quan trng trong la chn cc ligand cho cc v tr lin kt ca cc
enzym ng thi s c mt ca mt nhm Nitro vng A v nhm 9-metoxy
trn vng D ca indenoisoquinolin c mt tc ng tch cc ti hot tnh c
ch Tdp1 nh trnh by bng 1.2.1 cho 140 (+++), iu ny c th c
gii thch do to c nhiu lin kt hydro ca hp vi Top1 v DNA
[22,28,29].
Hnh 1.2.9: Lin kt hiro hnh thnh gia hp cht 140b trong phc hp
Top1-DNA-indenisoquinolin [22].
34
Mt iu tht th v l khi nghin cu cc indenoisoquinolin mch
nhnh N-(3-aminopropyl) c nhm th 9-metoxy vng D ch khc nhau
nhm th cacbon s 3 vng A th cho thy cc nhm ht electron 3-nitro c
hot tnh c ch Top1 mnh hn cc indenoisoquinolin c nhm th cacbon
s 3 l nhm iot hay amino 3-iot hoc 3-amino ch s IC50 ca cc hp cht
140a (3-NO2): ++++, 143 (3-I): +(+) v 140b (3-NH2): ++(+) [28].
OCH3 OCH3
O O
N N
I NH 2 H2 N NH 2. HCl
O O
143 144
35
u c hot tnh khi mch nhnh cha c 3-aminopropyl v nhm chc 11-
xeto.Tuy nhin nu thay nhm amin bng nhm OH ancol hay brom, azit,
morpholin, hoc imidazol cng to cc hp cht hot tnh yu hn hoc khng
c hot tnh hoc hot tnh ny gim mnh. Cc hp cht 145, 148 hu nh
khng c kh nng c ch Top1 v Tdp1 ( 145: 0, +; 148: 0, ++). Cc hp
cht 146, 147 cng c hot tnh rt yu hoc khng c hot tnh ( 146: 0; +++;
147: 0, +) [1,3,6].
Bng 1.2.1 : Hot tnh gy c (GI50 M) ca cc dn cht t 137-142.
Dng t bo ung th
Khi u Bung V Top1
Cht Phi Rut Thn MGM
c tnh trng MDA Tdp1 cleavag
th HOP- HCT- SN12 (M)
UACC- OVCA -MB- e
62 116 C
62 R-3 435
1.86 +(+)
137a 0.65 0.57 1.22 4.01 2.53 3.36 0
0.38
137 ++(+)
1.56 0.54 1.69 3.22 1.46 2.33 1.86 ++(+)
b
138 0.93 0.44 2.25 3.12 1.75 3.05 1.69 ++(+) ++(+)
0.17 ++
139 0.14 0.06 0.14 0.54 0.15 0.58 ++
0.017
0.02 +++
140 <0.01 <0.01 <0.01 2.82 <0.01 3.31 0.000 ++++
8
1.41 +++
141 1.15 0.72 2.34 2.29 7.08 1.62 ++++
0.43
0.15 +(+)
142 <0.01 0.03 0.08 <0.01 0.12 ++(+)
0.10
0.25 +++
143 0.14 0.07 0.14 1.32 0.05 0.96 +(+)
0.004
144 <0.01 <0.01 0.10 0.02 <0.01 0.12 0.04 +++ ++(+)
36
1.2.3. Hot tnh chng ung th ca cc hp cht indenoisoquinolin c nhm
th imetylaminopropyl vng B
Cc hp cht indenoisoquinolin c nhm th imetylaminopropyl vng B l
lp cht cho hot tnh gy c t bo ung th kh tt trong hp cht (6-(3-
(imetylamino)propyl)-9-metoxy-3-nitro-6H-indeno[1,2-c]isoquinolin-5,11-
ion (150): Khi nh nhm th metoxy v tr s 9 v nhm th nitro v tr s
3 vo hp cht 149 c chng minh l c s ci thin kh ln so vi hp
cht gc (6-(3-imetylamino)propyl)-9-metoxy-6H-indeno[1,2-c]isoquinolin-
5,11-ion (149) l kh nng gy c t bo mnh gp 93 ln (MGM
0,02M) v cung cp mt cht c ch Top1 mnh tng ng Camptothecin,
thm ch l mnh hn [1].
37
Bng 1.2.2: Hot tnh gy c (GI50 M) ca cc dn cht t 149-151.
Dng t bo ung th
Cht Khi u Bung V MGM Top1
Phi Rut
th HOP- HCT- c tnh trng Thn MDA- (M) cleavage
UACC- OVCAR- SN12C MB-
62 116
62 3 435
149 1,74 0,58 0,51 1,7 0,91 2,82 1,86 +++
150 <0,010 <0,010 <0,010 <0,010 0,028 <0,010 0,02 ++++
151 0,078 0,102 1,00 0,427 0,245 0,617 0,300 0
38
Hp cht 6-(3-(1H-imidazol-1-yl)propyl)-10-metoxy-3-nitro-6H-
indeno[1,2-c]isoquinolin-5,11-ion (153) nh nhm th nitro v nhm th
metoxy vo v tr s 3 v v tr s 10 ca hp cht gc c kh nng gy c t
bo gp 97 ln so vi hp cht chun 152 vi gi tr MGM 0,019M v l
cht gy c ch Top1 cc mnh. Mt s nng c ch tng trng GI50 ca
mt s loi t bo ung th c kim nghim v chng minh i cc dn
xut c nhm th imidazolyl propyl (bng 1.2.3)[1,6].
Bng 1.2.3: Hot tnh gy c (GI50 M) ca cc dn cht t 152 154
Dng t bo ung th
Cht Khi u Bung V MGM Top1
Phi Rut
th c tnh trng Thn MDA- (M) cleavage
HOP- HCT-
UACC- OVCAR- SN12C MB-
62 116
62 3 435
152 2,69 1,41 0,79 1,66 1,66 2,75 1,86 ++++
153 <0,010 <0,010 <0,010 0,02 <0,010 <0,010 0,019 ++++
154 0,056 0,11 0,071 1,66 0,676 0,646 0,416 +++
39
Hnh 1.2.14: Cc dn xut indenoisoquinolin c vng morpholinopropyl
[1,8,22]
Mt s nng c ch tng trng GI50 ca mt s loi t bo ung th
c kim nghim v chng minh i vi hp cht 155 158 (bng 1.2.4)
[1,8,22].
Bng 1.2.4: Hot tnh gy c (GI50 M) ca cc dn cht t 155 158
Dng t bo ung th
Cht Khi u V MGM Top1
Phi Rut Bung
th HOP- HCT- c tnh trng
Thn MDA- (M) cleavage
UACC- SN12C MB-
62 116 OVCAR-3
62 435
155 3,72 0 5,37 16,6 21,4 >100 15,1 ++
156 0,021 0,038 0,38 0 0,309 1,23 0,632 +++
157 <0,01 <0,01 <0,01 <0,01 <0,01 <0,01 0,014 ++++
158 1,41 1,26 1,58 2,69 4,07 4,68 2,7 +++
40
tng ng k trong hot tnh gy c nhng kh nng c ch Top1 rt t.
Thm vo l hp 6-(3-(Etylamino)propyl)-9-metoxy-3-nitro-(6H)-
indeno[1,2-c]isoquinolin-5,11-ion (160) l nh c nhm nitro v tr s 3 v
nhm metoxy vo v tr s 9 l tng ng k kh nng gy c t bo ln gp
21 ln so vi hp cht gc (159) vi gi tr MGM 0,016M v l cht c ch
Top1 kh mnh.
41
1.2.7. Hot tnh chng ng th ca cc indenoisoquinolin c cu trc
tng t nh Indotecan, Indimitecan
Cc indenoisoquinolin c cu trc tng t nh indotecan, indimitecan
c cc nh khoa hc M tin hnh nghin cu hot tnh chng ung th trn
60 dng t bo ung th khc nhau c ngun gc t cc khi u c th ngi.
Th nghim c tin hnh 5 nng khc nhau trong khong gii hn l
t 10-8M n 10-4M v s dng gi tr gy c t bo GI50 l nng tng
ng vi s c ch tng trng ln n 50%. MGM (Mean Graph Midpoint) l
cc gi tr th trung bnh da trn tnh ton ca gi tr GI50 trung bnh cho
tt c cc dng t bo th nghim (khong 60 dng) [8].
42
); ++ (gia 50% v 75% hot ng ); +++ (Gia 75% v 95% hot ng);
++++ (Tng ng); +++++ (Mnh hn nhiu). im khng r rng (gia
hai gi tr) c ch nh vi cc du ngoc n (v d, ++ (+) s vo khong
++ v +++). Cc s liu nghin cu c trnh by trong bng 1.2.6. Cc s
liu c thng k ti bng 1.2.6 cho thy tt c cc hp cht th nghim u
c kh nng c ch Top1. Tht vy, cc hp cht 164a, 164b, 165a c kh
nng c ch Top1 tng ng hoc ln hn so vi cc thuc ang c th
nghim lm sng l Indotecan v Indimitecan. Cc hp cht 166a v 166b c
kh nng gy c t bo trung bnh trn tt c cc dng t bo ung th kho
st (MGM) tt hn Indotecan v Indimitecan nhng hot tnh c ch Top1
yu hn cho thy kh nng s dng iu tr ko di tc dng chng khi u
trong c th ngi ca Indotecan, Indimitecan. Mc d trong thi gian gn
y c nhiu nghin cu nhm tm hiu mi tng quan gia cu trc ha hc
v hot tnh sinh hc ca indenoisoquinolin nhng vn cn nhiu iu tim n
bt ng nh 9-hydroxy-8-metoxyindenoisoquinolin 164a v 164b l cc
mnh th ng phn 8-hydroxy-9- metoxyindenoisoquinolin 163a v 163b c
hot tnh c ch Top1 gim i mt na v gi tr MGM u tng cao hn. S
tng quan v cu trc ha hc v hot snh sinh hc cng khng quan st
c khi thc hin cc thay i nhm th vng A, cc hp cht 2-
hydroxyindenoisoquinolin 165a v 3-hydroxyindenoisoquinolin 166b u c
hot tnh chng Top1 mt cch ng k, mc d c mt s khc bit gia
morpholin v imidazol c quan st thy. S gim hot tnh ca cc hp
cht 167a, 167b c th hiu c do c s thay th nhm xeton (C=O) v tr
th 11 bng nhm OH lm gim i s lin kt hydro ca nhm vi chui
bn ca Arg364 nhng s khc bit v hot snh sinh hc ca 2 nhm th
imidazol v morpholin cn l mt cu hi c t ra khi kh nng c ch
Top1 ca morpholin 168b ln gp i imidazol 168a th trong hp cht
morpholin 165a, imidazol 165b kt qu l ngc li [8].
43
Bng 1.2.6: Hot tnh gy c (GI50 M) ca cc dn cht t c cu trc
tng t nh indotecan, indimitecan .
Dng t bo ung th
Khi u Bung V
Cht Phi Rut MGM Top1
c tnh trng Thn MDA-
th HOP- HCT- (M) cleavage
UACC- OVCAR- SN12C MB-
62 116
62 3 435
0.079
6 <0.01 0.04 <0.01 0.08 <0.01 0.01 +++++
0.023
4.64
5 1.78 0.04 0.03 74.1 0.813 0.37 +++++
1.25
41.8
163a >100 0.331 >100 >100 0.05 ++(+)
7.15
3.07
163b 0.18 0.282 0.07 8.32 0.191 0.03 +++
0.32
0.055
164a <0.01 <0.01 <0.01 0.02 <0.01 <0.01 ++++(+)
0.003
0.087
164b 0.02 0.02 0.02 0.03 0.02 0.02 +++++
0.063
165a <0.01 <0.01 0.03 0.07 <0.01 0.049 +++++
0.412
165b 0.257 0.335 0.282 0.871 0.195 0.144 ++(+)
0.005
166a <0.01 <0.01 <0.01 0.03 <0.01 <0.01 0.043 ++++
166b 0.01 <0.01 <0.01 0.03 <0.01 <0.01 0.056 +++(+)
167a 0.549 0.479 0.372 1.95 0.501 0.427 1.66 ++
167b 2.09 2.4 0.776 4.79 3.39 0.646 3.16 ++
168a 0.04 0.01 <0.01 0.407 0.03 0.02 0.224 ++
168b 0.371 0.148 0.078 0.501 0.065 0.05 0.602 ++++
44
1.3. nh hng v mc tiu ca lun n
Nh vy, phn tng quan cho thy trong cc phng php tng hp
indenoisoquinolin th phng php tng hp thng qua phn ng ca
indeno[1,2-c]isochromen-5,11-ion (16) vi cc amin bc 1 thng c cc
nh khoa hc s dng nhiu hn v ch qua t bc phn ng, ng thi thun
li trong vic to ra nhiu dn xut khc nhau ca indenoisoquinolin
[1,2,4,12,13,15,28-33]. Nhng kt qu nghin cu ca cc nh khoa hc cng
ch ra rng cc hp cht indenoisoquinolin to c nhiu tng tc bn vng
vi DNA, protein v cc cp baz c s ti v tr phn ct ca topoisomerase I
thng c kh nng gy c t bo ung th cao hn [15,22,28,42]. Cc kt
qu nghin cu cng cho thy cc nhm th vng B cha cc d t cch
nguyn t nit ca vng indenoisoquinolin khong 3 nguyn t cacbon nh
cc nhm aminopropyl, imetylaminopropyl, imidazolopropyl,
morpholinopropyl cho kh nng gy c t bo rt tt tiu biu nh cc hp
cht ang c nghin cu s dng lm thuc chng ung th Indotecan (5) v
Indimitecan (6) [6,8,15,22,42,44].
45
CHNG 2: THC NGHIM
46
Ph IR ca cc cht nghin cu c xc nh trn my Impact 410-
Nicolet ti Vin Ho hc - Vin Hn lm Khoa hc & Cng ngh Vit Nam
v my FTIR Affinity-1S-SHIMADZU ti Khoa Ha hc Trng i hc
Khoa hc T nhin H Quc gia H Ni. Cc mu nghin cu c o
dng p vin vi KBr rn.
- Ph cng hng t ht nhn (NMR)
Ph 1H-NMR (500MHz) v 13C-NMR (125MHz) ca cc cht
nghin cu c o trn my Bruker XL-500 vi dung mi CDCl3 v TMS
l cht chun, ti phng Ph cng hng t ht nhn - Vin Ho hc - Vin
Hn lm Khoa hc & Cng ngh Vit Nam.
- Ph khi lng (MS)
Ph khi ESI-MS ca cc cht nghin cu c ghi trn LC- MSD-
Trap- SL ti trung tm nghin cu cu trc, Vin Ho hc- Vin Hn Lm
Khoa hc v Cng ngh Vit Nam.
- Kt qu X-ray tinh th
Kt qu X- ray tinh th c chp trn my Brucker D8-Quest ti khoa
Ha hc- i hc khoa hc t nhin H Ni. c c tnh ton v ti u
ha cu trc bng phng php Direct Method & SHEXT 2008 bi tc gi
Nguyn Hng Huy.
47
O O O
O
H 4,0 .l NaOMe 0,079 .l p-TsOH
+ O
OH
MeOH/EtOAc (2:1), O Toluen, , 6h O
O
O 65C, 6h O
OH 59
0C
56 57 58 60 OH
1,1 .l RNH2,
nhit phng,
F, CO
CH2 Cl2
169a R = 4-metoxybenzyl DM CH
24h
169m R = methyl (11H)-yl)undecanoat
169b R = 3-metoxybenzyl N R1
169c R = benzyl 169n R = 3-carboxypropyl H 2
169d R = 4-brombenzyl
169p R = 10-aminodecyl . l
169f R = 6-metoxypyridin-3-yl
170a R1 = hydro 1, 3
170b R1 = isopropyl
169g R = pyridin-2-ylmetyl
170c R1 = Bezyl
O O
169h R = furan-2-ylmetyl
170d R1 = 4-hydroxylbenzyl
169i R = prop-2-yn-1-yl
170e R1 = 3,4-dihydroxylbenzyl
169j R = allyl
169k R = 2-metoxyetyl H
169l R = 8-(N-Boc-amino)-3,6-dioxaoctanyl N C COOH N
169e R = 3- (N-Boc-N-metylamino)phenyl R1 R
O O
170 169
O O 173a X= Morpholin-1-yl O
173b X= 4-metylpiperidin-1-yl
173c X= piperidin-1-yl
OH
173d X= pyrrolidin-1-yl OH
173e X= 2-cyanoguanidyl
N N X N OCOR
173f X= azido
173g X= 4-Boc-piperazin-1-yl
O O 173h X= 4-methylpiperazin-1-yl
O 177a R = isopropyl
173i X= piperazin-1-yl 177 177b R = Metyl
169j 173
173j X= 4-tosylpiperazin-1-yl
(X = NR1R2)
O
O O 3,0 .l K2CO3
CH3CN/H 2O (40:1)
60 C,18h OH
Br + OH N OH
N Br N Br
O
O O
175
172 171
O O
OH OH
N SR N OSO 2R
48
2.2. Tng hp cc indenoisoquinolin trn c s ca phn ng gia
indeno[1,2-c]isochromen-5,11-ion vi cc amin bc 1.
2.2.1. Tng hp indeno[1,2-c]isochromen-5,11-ion (59)
49
132,67 (C-13); 131,64 (C-9); 130,87 (C-4); 128,39 (C-3); 123,30 (C-1);
123,15 (C-14); 119,82 (C-7); 118,97 (C-10); 107,71 (C-12).
14 N
3 OCH3
5 6
4
6' 5'
O
169a (H = 81%)
Dung dch ca 59 (100 mg; 0,4 mmol) trong CH 2Cl2 (5ml) c thm
4-metoxybenzylamin (60,07 mg; 0,44 mmol) v khuy ti nhit phng
trong 28h. Kt thc phn ng, hn hp sn phm c thm 30ml nc v
chit 3 ln trong dung mi CH2Cl2 (310ml). Dch chit c lm khan bng
Na2SO4, loi b dung mi bng my c ct quay chn khng thu c sn
phm th. Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi
h dung mi ra gii hexan/EtOAc (8:2) thu c sn phm 169a (120 mg),
hiu sut phn ng t 81%.
Hp cht 169a l cht rn c mu gch, c nhit nng chy l
203-204 oC.
1
H-NMR (500MHz, CDCl3) H ppm: 8,74 (1H, d, J = 8,0 Hz, H-1);
8,37 (1H, d, J = 8,0 Hz, H-4); 7,76 (1H, dt, J = 1,5; 8,0 Hz, H-2); 7,61 (1H,
dd, J = 1,0; 7,0 Hz, H-7); 7,49 (1H, dt, J = 1,5; 8,0 Hz, H-3) 7,26-7,36 (3H,
m, H-8; H-9; H-10); 7,17 (2H, d, J = 8,5Hz, H-3v H-5); 6,88 (2H, d, J =
8,5Hz, H-2v H-6); 5,73 (2H, s, NCH2); 3,76 (3H, s, OCH3).
50
13
C NMR (125 MHz, CDCl3) Cppm: 190,53 (C-11); 163,48 (C-5);
159,09 (C-4); 156,16 (C-15); 137,09 (C-16); 135,08 (C-17); 134,02 (C-2);
133,19(C-8); 132,43 (C-13); 130,88 (C-9);128,69 (C-4); 127,26 (C-3); 127,10
(C-2+ C-6); 123,58 (C-1);123,55 (C-14); 123,14 (C-7); 122,98 (C-10);
114,54 (C-3+C-5); 108,76 (C-12); 55,3 (OCH3); 47,7 (CH2).
IR (KBr): 3034; 2958; 2839; 1761; 1699; 1654; 1606; 1546; 1500;
1429; 1357; 1317; 1174; 1028; 815; 759 cm-1.
Dung dch ca 59 (50 mg; 0,2 mmol) trong CH2Cl2 (5ml) c thm 3-
metoxybenzylamin (30,035 mg; 0,22 mmol) v khuy ti nhit phng
trong 24h. Kt thc phn ng, hn hp sn phm c thm 30ml nc v
chit 3 ln trong dung mi CH2Cl2 (310ml). Dch chit c lm khan bng
Na2SO4, loi b dung mi bng my c ct quay chn khng thu c sn
phm th. Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi
h dung mi ra gii hexan/EtOAc (8:2) thu c sn phm 169b (66 mg),
hiu sut phn ng t 90%.
Hp cht 169b l cht rn c mu gch, c nhit nng chy l
182-183 oC.
1
H-NMR(500MHz, CDCl3) H ppm: 8,74 (1H, d, J = 8,0 Hz, H-1);
8,37 (1H, d, J = 8,0 Hz, H-4); 7,76 (1H, dt, J = 1,5; 8,0 Hz, H-2); 7,60 (1H, d,
J = 7,0 Hz, H-7); 7,50 (1H, td, J =1,5; 8,0 Hz, H-3); 7,23-7,32 (4H, m, H-8;
51
H-9; H-10, H-5); 6,80 (2H, d, J = 8,5 Hz, H-4, H-6), 6,75 (1H, s, H-2),
5,76 (2H, s, NCH2) 3,76 (3H, s, OCH 3).
2.2.2.3. Tng hp hp cht 6-benzyl-5H-indeno[1,2-c]isoquinolin-5,11(6H)-
ion (169c)
10
9
O 11
17 8
1 12 16
2 7 2' 3'
13 15
14
3 N
5 6
4
6' 5'
O
169c (H=90%)
Dung dch ca 59 (50 mg; 0,2 mmol) trong CH2Cl2 (5ml) c thm
benzylamin (23,508 mg, 0,22 mmol) v khuy ti nhit phng trong 24h.
Kt thc phn ng, hn hp sn phm c thm 30ml nc v chit 3 ln
trong dung mi CH2Cl2 (310ml). Dch chit c lm khan bng Na2SO4,
loi b dung mi bng my c ct quay chn khng thu c sn phm th.
Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi h dung
mi ra gii n-hexan/EtOAc (8:2) thu c sn phm 169c (60 mg), hiu sut
phn ng t 90%.
Hp cht 169c l cht rn c mu gch, c nhit nng chy l
199-200 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,75 (1H, d, J = 8,0 Hz, H-1);
8,38 (1H, d, J = 7,0 Hz, H-4), 7,77 (1H, dt, J = 1,5; 7,5 Hz, H-2); 7,50 (1H,
dt, J = 1,5; 7,5 Hz, H-3); 7,26-7,37 (8H, H-8, H-9, H-10, H-2, H-3, H-4, H-
5, H-6), 5,76 (2H, s, NCH2).
52
2.2.2.4. Tng hp 6-(4-brombenzyl)-5H-indeno[1,2-c]isoquinolin-5,11(6H)-
ion
Ha tan hon ton cht 59 (50,0 mg; 0,20 mmol) trong CH2Cl2 (2 ml),
sau b sung 4-bromobenzylamin (40,9 mg; 0,22 mmol) vo hn hp trn.
Hn hp c khuy u trong 24 gi nhit phng. Kt thc phn ng,
hn hp sn phm c thm 30ml nc v chit 3 ln trong dung mi
CH2Cl2 (310ml), lm kh bng Na2SO4, ct loi dung mi bng my ct
quay chn khng thu c sn phm th. Sn phm th c lm sch bng
sc k ct silica gel vi h dung mi ra gii hexan/EtOAc (8:2) c c
hp cht 169d (70,7 mg) vi hiu sut phn ng 85%.
Hp cht 169d l cht rn c mu cam, c nhit nng chy l 198-
199 oC
1
H NMR (500 MHz, CDCl3) H ppm: 8,73 (1H, d, J = 8,0 Hz, H-1); 8,37
(1H, dd, J = 0,5; 8,0 Hz, H-4); 7,76 (1H, dt, J = 1,5; 8,0 H-2); 7,60 (1H, d, J
= 7,0 Hz, H-7); 7,46-7,50 (3H, m, H-3, H-5 v H-3); 7,32 (1H, dt, J = 1,0;
7,0 Hz; H-8); 7,23-7,28 (2H, m, H-9, H-10); 7,12 ( 2H, d, J = 8,5 Hz, H-2,
H-6); 5.72 (2H, s, NCH 2).
13
C NMR (125 MHz, CDCl3) c ppm: 190,4 (C-11); 163,4 (C-5); 155,7
(C-15); 136,8 (C-16); 134,9 (C-17); 134,5 (C-1); 134,2 (C-2); 133,25 (C-8);
132,41 (C-13); 132,29 (C-3+C-5); 131,04 (C-9);128,71 (C-4); 127,53 (C-
2+ C-6); 127,45 (C-3); 123,66 (C-1);123,45 (C-14) 123,34 (C-7); 122,57
(C-10); 121,68 (C-4); 108,93 (C-12); 47,69 (CH2).
53
IR (KBr): 3068; 2924; 2852; 1701; 1651; 1604; 1546; 1496; 1456;
1425; 1068; 962; 873; 794; 754; 698 cm-1.
2.2.2.5. Tng hp 6-(3-(N-Boc-N-Metylamino)phenzyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (169e)
Ha tan hon ton cht 59 (50,0 mg; 0,20 mmol) trong CH 2Cl2 (2 ml),
sau b sung tert-butyl (3-aminophenyl)(metyl)cacbamat (48,84 mg; 0,22
mmol) trong 1 ml DMF vo hn hp trn. Hn hp c khuy u trong 29
gi nhit phng. Kt thc phn ng, hn hp sn phm c thm 30ml
nc v chit 3 ln trong dung mi CH 2Cl2 (310ml), lm kh bng Na2SO4,
ct loi dung mi bng my ct quay chn khng thu c sn phm th. Sn
phm th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (3:7) c c hp cht 169e (73,2 mg) vi hiu sut phn
ng 81%.
Hp cht 169e l cht rn c mu cam, c nhit nng chy l
204-205 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,72 (1H, d, J = 8,0 Hz, H-1);
8,35 (1H, dd, J = 0,5; 7,5 Hz, H-4); 7,76 (1H, dt, J= 1,0; 8,0 Hz, H-2); 7,53-
7,59 (3H, m, H-4, H-5, H-7); 7,48 (1H, t, J = 7,5 Hz, H-3); 7,38 (1H, s, H-
2); 7,26-7,21 (2H, m, H-8, H-10); 7,02 (1H, t, J= 7.5 Hz, H-9); 5,66 (1H, d, J
= 7,5 Hz, H-6); 3,32 (3H, s, N-CH3); 1,41 (9H, s, 3CH3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,7 (C-11); 163,6 (C-5); 155,3
(C-15); 154.2 (COOC(CH3)3); 145.5 (C-3); 137.5 (C-1); 137.1 (C-16);
134.8 (C-17); 134,37 (C-2); 132,89 (C-8); 132,86 (C-13); 130,88 (C-9);
54
129,99 (C-5); 128,85 (C-4); 127,45 (C-3); 126,66 (C-2); 125,56 (C-6);
125,14 (C-4); 124,16 (C-1); 123,83 (C-14) 122,92 (C-7); 122,72 (C-10);
108,93 (C-12); 81,1 (C-(CH 3)3); 37,3 (CH3-N); 28,5 (3CH3).
IR (KBr): 3062; 2974; 2929; 1693; 1662; 1608; 1573; 1546; 1496;
1454; 1413; 1361; 1149; 788; 765; 748; 669 cm-1.
Ha tan hon ton 59 (50 mg; 0,2 mmol) trong 2ml CH2Cl2, sau b
sung 5-amino-2-metoxypyridin (27,5 mg, 0,22 mmol) vo hn hp trn. Hn
hp c khuy v duy tr nhit phng trong 26h. Kt thc phn ng,
hn hp c chit bng CH2Cl2, lm kh bng Na2SO4, quay kh thu c
sn phm th. Sn phm th c lm sch bng sc k ct silica gel vi h
dung mi ra gii hexan/EtOAc (6:4) thu c sn phm 169f (59,1 mg) c
mu cam vi hiu sut phn ng 83 %.
Hp cht 169f l cht rn c mu gch, c nhit nng chy l
253-254 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,72 (1H, d, J = 8,0 Hz, H-1);
8,21 (1H, d, J = 2,5, H-2); 8,34 (1H, d, J = 8,0 Hz, H-4); 7,77 (1H, td, J =
1,0; 8,0 Hz, H-2); 7,65 (1H, dd, J = 2,5; 8,5 Hz, H-6); 7,57 (1H, d, J = 8,0
Hz, H-7); 7,49 (1H, td, J = 2,5; 8,0 Hz, H-3); 7,26 (1H, td, J = 2,5; 7,5 Hz, H-
55
8); 7,10 (1H, t, J = 0,5; 7,5 Hz, H-9); 7,01 (1H, d, J = 8,5 Hz, H-10); 5,80
(1H, d, J = 7,5, H-5); 4,08 (3H, s, OCH 3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,52 (C-11); 164,66 (C-4,
N=COCH 3); 163,80 (C-5); 155,33 (C-15); 145,5 (C-2); 138,8 (C-1); 137,04
(C-16); 134,68(C-17); 134,38 (C-2); 132,84 (C-8); 132,72 (C-13); 130,87 (C-
9);128,79 (C-4); 127,78 (C-6); 127,45 (C-3); 123,85 (C-1); 123,76 (C-14)
123,04 (C-7); 122,24 (C-10); 112,06 (C-5); 108,93 (C-12); 54,19 (OCH3).
IR (KBr): 3076; 2943; 1789; 1693; 1662; 1606; 1573; 1548; 1485; 1411;
1375; 1182; 1012; 817; 759 cm-1.
2.2.3.2. Tng hp cht 6-(pyridin-2-ylmetyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (169g)
Ha tan hon ton 59 (50 mg; 0,2 mmol) trong 2ml CH2Cl2, sau b
sung 2-pyridinmetylamin (24 mg; 0,22 mmol) vo hn hp trn. Hn hp
c khuy v duy tr nhit phng trong 28h. Kt thc phn ng, hn
hp sn phm c thm 30ml nc v chit 3 ln trong dung mi CH2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (7:3) thu c sn phm 169g (58,13 mg) c mu cam vi
hiu sut phn ng 86 %.
Hp cht 169g l cht rn c mu gch, c nhit nng chy l
231-232 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,74 (1 H, d, J = 8,0 Hz, H-1);
8,61 (1 H, d, J = 4,5 Hz, H-3); 8,39 (1 H, d, J = 8,0 Hz, H-4); 7,77 (1 H, dt, J
56
= 1,5; 8,0 Hz, H-2); 7,64 (1 H, dt, J = 2,0; 8,0Hz, H-5); 7,58 (1 H, dd , J =
1,0; 7,0Hz, H-7); 7,48-7,51 (2 H, t, J = 8,0 Hz, H-3, H-8); 7,19-7,30 (4 H, m,
H-9, H-10, H-4, H-6); 5,90 (2H, s, CH 2).
13
C NMR (125 MHz, CDCl3) c ppm: 190,52 (C-11); 163,5 (C-5);
155,5 (C-15); 149,6 (C-1); 137,4 (C-3); 137,05 (C-16); 134,92 (C-5);
134,51 (C-17); 134,17 (C-2); 133,26 (C-8); 132,58 (C-13); 130,82 (C-9);
128,73 (C-4); 127,38 (C-3); 125,94 (C-6); 123,68 (C-1); 123,25 (C-14)
123,11 (C-7); 122,75 (C-10); 120,94 (C-4); 108,91 (C-12); 49,6 (CH 2).
IR (KBr): 3064; 2945; 1761; 1701; 1647; 16606; 1546; 1500; 1423;
1315; 1263; 1190; 1159; 1049; 798; 756 cm-1.
2.2.3.3. Tng hp hp cht 6-(furan-2-ylmetyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (169h)
Ha tan hon 59 (30 mg; 0,12 mmol) trong 2ml CH 2Cl2, sau b sung
1-(2-Furyl)metylamin (13 mg; 0,133 mmol) vo hn hp trn. Hn hp c
khuy v duy tr nhit phng trong 30h. Kt thc phn ng, hn hp sn
phm c thm 30ml nc v chit 3 ln trong dung mi CH 2Cl2 (310ml),
lm kh bng Na2SO 4, quay kh thu c sn phm th. Sn phm th c
lm sch bng sc k ct silica gel vi h dung mi ra gii hexan/EtOAc
(6:4) thu c sn phm 169h (32,59 mg) c mu cam vi hiu sut phn
ng 83 %.
Hp cht 169h l cht rn c mu gch, c nhit nng chy l 237-
238 oC.
57
1
H NMR (500 MHz, CDCl3) H ppm: 8,71 (1H, d, J = 8,0 Hz, H-1);
8,38 (1H, d, J = 8,0 Hz, H-4); 7,73 (1H, dt, J = 1,5; 8,0 Hz, H-2); 7,68 (1H, d,
J = 7,0 Hz, H-7); 7,62 (1H, dd, J = 1,0; 7,0 Hz, H-10); 7,47 (1H, t, J = 8,0
Hz, H-3); 7,37-7,41 (3H, m, H-8, H-9, H-3); 6,40 (1H, d, J = 3,0 Hz, H-5);
6,35 (1H, dd, J = 2,0; 3,5 Hz, H-4); 5,72 (2H, s, CH 2).
IR (KBr): 3064; 2931; 1759; 1695; 1653; 1606; 1546; 1500; 1458; 1419;
1346; 1315; 1261; 1157; 1049; 1002; 800; 756 cm-1
Ha tan hon ton cht 83 (90 mg; 0,36 mmol) trong 5ml CH2Cl2, sau
b sung 3-aminoprop-1-in (24 mg; 0,435 mmol) vo hn hp trn. Hn
hp c khuy v duy tr nhit 20 oC trong 22 gi. Kt thc phn ng,
b sung 45 ml CH2Cl2 (3 ln 15 ml) vo hn hp, chit vi 25 ml nc, lm
kh bng Na2SO4, ct loi dung mi bng my ct quay chn khng thu c
sn phm th. Sn phm th c lm sch bng sc k ct silica gel vi h
dung mi ra gii hexan/EtOAc (8:2) thu c sn phm 169i (91,02 mg) c
mu cam vi hiu sut phn ng 81%.
Hp cht 169i l cht rn c mu vng cam, c nhit nng chy l
226-227 oC.
58
1
H-NMR (500MHz, CDCl3&DMSO) H ppm: 8,62 (1H, d, J = 8,0 Hz,
H-1); 8,31 (1H, d, J = 8,0 Hz, H-4); 7,77 (1H, d, J = 7,5 Hz, H-7); 7,70 (1H, t,
J = 8,0 Hz, H-2); 7,56 (1H, d, J = 7,0 Hz, H-10); 7,43-7,47 (2H, m, H-8; H-
3); 7,38 (1H, t, J = 7,0 Hz, H-9); 5,27 (2H, s, 2H-1); 2,49 (1H, s, H-3).
13
C NMR (125 MHz, CDCl3&DMSO) c ppm: 13C NMR (125 MHz,
CDCl3) c ppm: 189,99 (C-11); 162,20 (C-5); 154,94 (C-15); 136,50(C-16);
134,49 (C-17); 133,79(C-2); 133,04 (C-8); 131,99 (C-13); 130,82 (C-9);
128,36 (C-4); 127,02 (C-3); 123,25 (C-1); 123,14 (C-14) 122,87 (C-7);
122,82 (C-10); 108,59 (C-12); 77,18 (C-2); 74,32 (C-3); 34,22 (C-1);
IR (KBr): 3244; 3078; 2958; 2924; 2117; 1745; 1697; 1658; 1604; 1571;
1544; 1496; 1423; 1311; 1261; 1190; 1020; 970; 927; 754; 713 cm-1
2.2.4.1. Tng hp cht 6-allyl-5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion
(169j).
Ha tan hon ton cht 59 (90 mg; 0,36 mmol) trong 5ml CH2Cl2, sau
b sung 3-aminoprop-1-en (22,58 mg, 0,396 mmol) vo hn hp trn. Hn
hp c khuy v duy tr nhit 20 oC trong 22 gi. Kt thc phn ng,
b sung 45 ml CH2Cl2 (3 ln 15 ml) vo hn hp, chit vi 25 ml nc, lm
kh bng Na2SO 4, ct loi dung mi bng my ct quay chn khng thu c
sn phm th. Sn phm th c lm sch bng sc k ct silica gel vi h
dung mi ra gii hexan/EtOAc (8:2) thu c sn phm 169j (96,68 mg) c
mu cam vi hiu sut phn ng 92 %.
Hp cht 169j l cht rn c mu thm, c nhit nng chy l
154-155 oC.
59
1
H NMR (500 MHz, CDCl3) H ppm: 8,68 (1H, d, J = 8,0Hz, H-1);
8,32 (1H, d, J = 8,0 Hz, H-4); 7,71 (1H, t, J = 8,0 Hz, H-2); 7,58 (1H, d, J =
7,0 Hz, H-7); 7,45-7,33 (4H, m, H-3, H-8, H-9, H-10); 6,11 (1H, m, H-2);
5,30 (1H, td, J = 1,5; 10,5Hz, Ha-3); 5,21-5,15 (3H, m, Hb-3, 2H-1).
13
C NMR (125 MHz, CDCl3) c ppm: 190,43 (C-11); 163,10 (C-5);
155,79 (C-15); 136,89 (C-16); 134,47 (C-17); 133,93 (C-2); 133,08 (C-8);
132,30 (C-2) 131,39 (C-13); 130,92 (C-9); 128,57 (C-4); 127,18 (C-3);
123,49 (C-1); 123,10 (C-14) 122,92 (C-7); 122,65 (C-10); 117,40 (C-
3);108,99 (C-12); 46,41 (C-1).
IR (KBr): 3061; 2924; 2852; 1766; 1689; 1662; 1606; 1571; 1546;
1498; 1421; 1377; 1313; 1068; 960; 798; 750 cm-1
Ha tan hon ton 83 (30 mg, 0,12 mmol) trong 2ml CH2Cl2, sau b
sung 2-metoxyetylamin (10 mg, 0,13 mmol) vo hn hp trn. Hn hp c
khuy v duy tr nhit phng trong 23h. Kt thc phn ng, hn hp sn
phm c thm 30ml nc v chit 3 ln trong dung mi CH2Cl2 (310ml),
lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm th c
lm sch bng sc k ct silica gel vi h dung mi ra gii hexan/EtOAc
(8:2) thu c sn phm 169k (35,2 mg) vi hiu sut phn ng 96%.
Hp cht 169f l cht rn c mu cam, c nhit nng chy l
175-176 oC.
60
1
H NMR (500 MHz, CDCl3) H ppm: 8,71 (1H, d, J = 8,0 Hz, H-1);
8,33 (1H, d, J = 8,0 Hz, H-4); 7,72 (2H, t, J = 7,5Hz, H-2, H-3); 7,62 (1H, d, J
= 7,0 Hz, H-7); 7,47 (2H, m, H-8, H-10); 7,39 (1H, t, J = 7,0 Hz, H-9); 4,73
(2H, t, J = 6,5 Hz, C-1); 3,86 (2H, t, J = 6,5 Hz, C-2); 3,38 (3H, s, OCH3).
Dung dch ca 59 (50 mg; 0,2 mmol) trong CH2Cl2 (5ml) c thm
tert-butyl 2-(2-ethoxyethoxy)Etylcarbamat (54,6 mg, 0,22 mmol) v khuy ti
nhit phng trong 30h. Kt thc phn ng, hn hp sn phm c thm
30ml nc v chit 3 ln trong dung mi CH2Cl2 (310ml). Dch chit c
lm khan bng Na2SO4, loi b dung mi bng my c ct quay chn khng
thu c sn phm th. Sn phm th c tinh ch, lm sch bng sc k ct
silica gel vi h dung mi ra gii n-hexan/EtOAc (7:3) thu c sn phm
169l (82,2 mg), hiu sut phn ng t 86%.
IR (KBr): 3358; 3064; 2958; 2924; 2856; 1695; 1658; 1608; 1575; 1548;
1500; 1456; 1425; 1363; 1315; 1249; 1166; 1105; 1058; 875; 756; 693 cm-1.
61
2.2.4.4. Tng hp 6-(Metyl (11H)-yl)undecanoat)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (169m)
Dung dch ca 59 (50 mg; 0,2 mmol) trong CH2Cl2 (2ml) c thm
metyl 11-aminoundecanoat (47,3 mg; 0,22 mmol) v khuy ti nhit phng
trong 26h. Kt thc phn ng, hn hp sn phm c thm 30ml nc v
chit 3 ln trong dung mi CH2Cl2 (310ml). Dch chit c lm khan bng
Na2SO4, loi b dung mi bng my c ct quay chn khng thu c sn
phm th. Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi
h dung mi ra gii n-hexan/EtOAc (6:4) thu c sn phm 169m (56,9
mg), hiu sut phn ng t 82%.
IR (KBr): 3040; 2972; 2916; 2850; 1724; 1695; 1658; 1608; 1575; 1548;
1502; 1465; 1427; 1373; 1321; 1240; 1193; 1099; 1074; 881; 756; 696 cm-1
62
2.2.4.5. Tng hp 4-(5,11-ioxo-5,11-ihydro-6H-indeno[1,2-c]isoquinolin-
6-yl)butanoic axt (169n).
10
9
O
11
17 8
1
12 16
2 7
13 15
2'
14 N COOH
3
5 6 1' 3'
4
O 169n (H=81%)
Dung dch ca 59 (50 mg; 0,2 mmol) trong CH2Cl2 (2ml) c thm 4-
aminobutanoic axt (22,66 mg; 0,22 mmol), b sung thm 0,3 ml MeOH v
khuy ti nhit 500 trong 30h. Kt thc phn ng, hn hp sn phm c
c ui MeOH, sau thm 30ml nc v chit 3 ln trong dung mi CH 2Cl2
(310ml). Dch chit c lm khan bng Na2SO4, loi b dung mi bng
my c ct quay chn khng thu c sn phm th. Sn phm th c tinh
ch, lm sch bng sc k ct silica gel vi h dung mi ra gii n-
hexan/EtOAc (6:4) thu c sn phm 169n (53,9 mg), hiu sut phn ng
t 81%.
Hp cht 169n l cht rn cam, c nhit nng chy l 185-186
o
C.
1
H NMR (500 MHz, CDCl3) H ppm: 8,61 (1H, d, J = 8,5Hz, H-1); 8,23
(1H, d, J = 8,0 Hz, H-4); 7,78 (1H, d, J = 7,5 Hz, H-7); 7,66 (1H, dt, J = 1,5;
8,0 Hz, H-2); 7,55 (1H, d, J = 7,0 Hz, H-10); 7,39-7,44 (2H, m, H-3, H-8);
7,33 (1H, t, J = 7,0 Hz, H-9); 4,54 (2H, t, J = 7,5 Hz, NCH2 ); 2,52 (2H, t, J =
7,0 Hz, HOOCCH2); 2,11 (2H, m, HOOCCH 2CH 2CH2N).
63
2.2.4.6. Tng hp cht 6-(10-aminodecyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (169p).
Ha tan hon ton 59 (50 mg; 0,2 mmol) trong 2ml CH2Cl2, sau b
sung 1,10-iaminodecane (51,6 mg; 0,3 mmol) vo hn hp trn. Hn hp
c khuy v duy tr nhit phng trong 28h. Kt thc phn ng, hn
hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (1:1) thu c sn phm 169p (64,3 mg) c mu cam vi
hiu sut phn ng 80 %.
1
H NMR (500 MHz, CDCl3) H ppm: 8,71 (1H, d, J= 8,0 Hz, H-1);
8,34 (1H, d, J = 8,0 Hz, H-4); 7,73 (1H, t, J = 8,0 Hz, H-2); 7,64 (1H, d, J =
7,0 Hz, H-7); 7,47 (3H, m, H-3, H-8, H-10); 7,41 (1H, dt, J= 1,5; 7,0 Hz, H-
9); 4,50 (2H, t, J = 7,5 Hz, 2H-1); 3,25 (2H, q, J= 7,0, 13,5 Hz, 2H-10);
1,94-1,87 (2H, m, 2H-2); 1,57-1,47 (4H, m, 2H-3+2H-9); 1,44-1,39 (2H,
m, 2H-8); 1,38-1,27 (8H, m, 2H-4+ 2H-5+2H-6+2H-7).
13
C NMR (125 MHz, CDCl3) c ppm: 190,40 (C-11); 163,38 (C-5);
155,57 (C-15); 137,20 (C-16); 135,28 (C-17); 133,19 (C-2); 133,08 (C-8);
132,25 (C-13); 130,97 (C-9); 128,39 (C-4); 127,11 (C-3); 123,47 (C-14, C-1);
123,21 (C-7); 122,33 (C-10); 108,99 (C-12); 44,71 (C-1); 39,67 (C-10);
29,58 ; 29,35; 29,32; 29,28 ; 29,16; 26,83 ; 26,76.
64
2.2.5. Tng hp cc indenoisoquinolin 170 trn c s ca phn ng gia
indeno[1,2-c]isochromen-5,11-ion vi cc -amino axt.
Dung dch ca 59 (100 mg, 0,4 mmol) trong DMF (5ml) c cho thm
Glyxin (33 mg; 0,44 mmol) v khuy 60oC trong 24h. Kt thc phn ng,
hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH 2Cl2
(310ml). Dch chit c ra nhiu ln bng dung dung dch HCl 5%, sau
lm khan bng Na2SO4, loi b dung mi p sut thp thu c sn
phm th. Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi
h dung mi ra gii (etyl axetat/MeOH) (8:2) thu c sn phm 170a
(107,36 mg), hiu sut phn ng t 88%.
Hp cht 170a l cht rn c mu vng cam, c nhit nng chy l
286-287 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,65 (1H, d, J = 8,0 Hz, H-1);
8,29 (1H, d, J = 8,0 Hz, H-4); 7,72 (1H, dt, J = 1,5; 8,0 Hz, H-2); 7,58 (1H, d,
J = 6,5 Hz, H-7); 7,44 (1H, dt, J = 1,0; 8,0 Hz, H-3); 7,32-7,38 (3H, m, H-8,
H-9, H-10); 5,27 (2H, s, NCH2).
13
C NMR (125 MHz, CDCl3) c ppm: 190,40 (C-11); 169,33 (COOH);
163,42 (C-5); 155,79 (C-15); 137,06 (C-16); 134,63 (C-17); 134,21 (C-2);
133,41 (C-8); 132,38 (C-13); 131,08 (C-9); 128,44 (C-4); 127,35 (C-3);
65
123,46 (C-1); 123,30 (C-14); 123,09 (C-7); 121,83 (C-10); 108,86 (C-12);
45,81 (CH2).
IR (KBr): 3414; 3022; 2929; 2848; 2850; 1737; 1695; 1645; 1606; 1573;
1546; 1498; 1456; 1417; 1379; 1313; 1240; 1192; 1099; 1080; 962; 750; 694
cm-1.
Dung dch ca 59 (50 mg; 0,2 mmol) trong DMF (5ml) c cho thm
L-Valin (25,7 mg; 0,22 mmol) v khuy 60oC phng trong 24h. Kt thc
phn ng, hn hp sn phm c thm 30ml nc v chit 3 ln vi dung
mi CH 2Cl2 (310ml). Dch chit c ra bng HCl 5% v lm khan bng
Na2SO4, loi b dung mi p sut thp thu c sn phm th. Sn phm
th c tinh ch, lm sch bng sc k ct silica gel vi h dung mi ra
gii EtOAc/MeOH (9:1) thu c sn phm 170b (59,68 mg), hiu sut phn
ng t 86%.
Hp cht 170b l cht rn c mu c rt, c nhit nng chy l
168-169 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,45 (1H, d, J = 8,0 Hz, H-1),
8,00 (1H, d, J = 8,0 Hz, H-4), 7,57 (1H, d, J = 7,0 Hz, H-7); 7,50 (1H, t, J =
8,0 Hz, H-2) 7,17-7,44 (4H, m, H-3; H-8; H-9; H-10); 4,64 (1H, d, J = 9,5 Hz,
NCHCOOH); 2,84 (1H, m, CHCH(CH3)2); 1,13 (3H, d, J = 5,5 Hz,
CH(CH3)a); 0,51(3H, d, J = 6,5 Hz, CH(CH3)b).
66
IR (KBr): 3390; 2958; 2926; 2866; 2358; 1728; 1701; 1645; 1606; 1546;
1498; 1456; 1379; 1317; 1271; 1195; 1078; 1080; 993; 760; 700 cm-1.
Dung dch ca 59 (50 mg; 0,2 mmol) trong DMF (5ml) c cho thm
L-Phenyl alanin (36,3 mg; 0,22 mmol) v khuy 60oC phng trong 22h. Kt
thc phn ng, hn hp sn phm c thm 30ml nc v chit 3 ln vi
dung mi CH 2Cl2 (310ml). Dch chit c ra bng HCl 5% v lm khan
bng Na2SO4, loi b dung mi p sut thp thu c sn phm th. Sn
phm th c tinh ch, lm sch bng sc k ct silica gel vi h dung mi
ra gii EtOAc/MeOH (9:1) thu c sn phm 170c (67,15 mg), hiu sut
phn ng t 85%.
Hp cht 170c l cht rn c mu thm, c nhit nng chy l
124-125 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,51 (1H, d, J = 8,0 Hz, H-1),
8,16 (1H, d, J = 8,0 Hz, H-4), 7,62 (1H, J = 7,0 Hz, H-7); 7,31-7,36 (2H, m,
H-2, H-3); 7,05-7,12 (3H, m, H-8, H-9, H10); 6,83-6,94 (5H, m, H-2, H-
3, H-4, H-5, H-6); 5,33 (1H, m, H-1); 3,56 (1H, d, J = 7,0 Hz, H a-2);
3,24 (1H, d, J = 1,5 Hz, H b-2).
IR (KBr): 3385; 2956; 2924; 2854; 2358; 1726; 1697; 1647; 1604; 1570;
1544; 1498; 1450; 1411; 1379; 1197; 1024; 754; 700 cm-1.
67
2.2.5.4.Tng hp hp cht axt (S)-2-(5,11-ioxo-5H-indeno[1,2-
c]isoquinolin-6(11H)-yl)-3-(4-hydroxyphenyl) propanoic (170d)
Dung dch ca 59 (50 mg; 0,2 mmol) trong DMF (5ml) c cho thm
L-Tyrosin (39,8 mg; 0,22 mmol) v khuy 60oC phng trong 23h. Kt thc
phn ng, hn hp sn phm c thm 30ml nc v chit 3 ln vi dung
mi CH 2Cl2 (310ml). Dch chit c ra bng HCl 5% v lm khan bng
Na2SO4, loi b dung mi p sut thp thu c sn phm th. Sn phm
th c tinh ch, lm sch bng sc k ct silica gel vi h dung mi ra
gii EtOAc/MeOH (85:15) thu c sn phm 170d (66,58 mg), hiu sut
phn ng t 81%.
Hp cht 170d l cht rn c mu thm, c nhit nng chy l
183-184 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,53 (1H, d, J = 8,0 Hz, H-1), 8,16
(1H, d, J = 7,5 Hz, H-4), 7,60 (1H, t, J = 7,5; 8,0 Hz, H-2); 7,47 (1H, t, J =
7,5 Hz, H-3); 7,33 (1H, d, J = 7,0 Hz, H-7); 7,18 (1H, d, J = 7,0 Hz, H-10);
7,08 (1H, t, J = 7,5 Hz, H-8); 7,00 (1H, t, J = 7,5 Hz, H-9); 6,63 (2H, d, J =
8,0 Hz, H-2 v H-6); 6,30 (2H, J = 8,0 Hz, H-3 v H-5); 5,30 (1H, m,
H-1); 5,30 (1H, m, H-1); 3,60 (1H, d, J = 10,0 Hz, H a-2); 3,48 (1H, d, J =
11,0 Hz, H b-2).
IR (KBr): 3373; 2918; 2850; 1691; 1654; 1600; 1546; 1514; 1498; 1458;
1411; 1379; 1246; 1201; 1022; 813; 758; 694 cm-1.
68
2.2.5.5. Tng hp hp cht axt (S)-3-(3,4-ihydroxyphenyl)-2-(5,11-ioxo-
5,11-ihydro-6H-indeno[1,2-c]isoquinolin-6-yl)propanoic (170e)
Dung dch ca 59 (50 mg; 0,2 mmol) trong DMF (5ml) c cho thm
3,4-ihydroxyphenylalanin (94 mg; 0,22 mmol) v khuy 60oC phng trong
25h. Kt thc phn ng, hn hp sn phm c thm 30ml nc v chit 3
ln vi dung mi CH2Cl2 (310ml). Dch chit c ra bng HCl 5% v lm
khan bng Na2SO 4, loi b dung mi p sut thp thu c sn phm th.
Sn phm th c tinh ch, lm sch bng sc k ct silica gel vi h dung
mi ra gii EtOAc/MeOH (90:10) thu c sn phm 170e (69,20 mg), hiu
sut phn ng t 80%.
69
2.3. Tng hp cc indenoisoquinolin i t 6-allyl-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion.
2.3.1. Tng hp cht 171 v hp cht 172.
Ha tan hon ton cht 169j (96,68 mg; 0,336 mmol) trong 5 ml
CH2Cl2, lm lnh hn hp phn ng ti 0 oC, b sung 0,012 ml H2O, nh t
t 0,035 ml Br2 vo hn hp phn ng. Hn hp c khuy v duy tr
nhit 0-5 oC trong 3 gi. Kt thc phn ng, hn hp c b xung 15 ml
NaOH 30%, lc u trong vng 5 pht ri chit bng CH2Cl2, lm kh bng
Na2SO4, quay kh thu c sn phm th. Sn phm th c lm sch bng
sc k ct silica gel vi h dung mi ra gii hexan/EtOAc (9:1) thu c sn
phm 172 (15 mg) vi hiu sut phn ng 10% v h dung mi ra gii
hexan/EtOAc (7:3) thu c sn phm 12 (99,3 mg) vi hiu sut phn ng
77 %.
* Hp cht 6-(3-bromo-2-hydroxypropyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (171)
Hp cht 171 l cht rn c mu , c nhit nng chy 176-177 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,71 (1H, d, J = 8,0 Hz, H-1);
8,31 (1H, dd, J = 1,0; 8,0 Hz, H-4); 7,83 (1H, d, J = 7,5 Hz, H-7); 7,65 (1H, t,
J = 8,0 Hz, H-2); 7,52 (1H, t, J = 8,0 Hz, H-3); 7,37-7,42 (2H, m, H-8, H-10);
7,31 (1H, t, J=7,5 Hz, H-9); 4,70 (1H, dd, J= 4,5, 14,5 Hz, Ha-1); 4,60 (1H,
dd, J = 8,0, 14,5 Hz, H b-1); 4,36-4,40 (1H, m, H-2); 3,67 (2H, dd, J=6,5,
11,5 Hz, H-3).
70
13
C NMR (125 MHz, CDCl3& MeOD) c ppm: 190,81 (C-11); 164,49
(C-5); 156,07 (C-15); 137,19 (C-16); 134,70 (C-17); 134,14 (C-2); 133,28 (C-
8); 132,27 (C-13); 130,89 (C-9); 128,18 (C-4); 127,26 (C-3); 123,67 (C-1);
123,43 (C-14) 123,09 (C-7); 122,57 (C-10); 109,02 (C-12); 69,07 (C-2);
48,86 (C-1); 36,60 (C-3).
IR (KBr): 3412; 2970; 2931; 1695; 1641; 1608; 1573; 1546; 1496;
1413; 1311; 1261; 1192; 1047; 1004; 796; 746; 692; 578 cm-1
* Hp cht 6-(2,3-ibromopropyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (172)
Hp cht 172 l cht rn c mu tm, c nhit nng chy 150-151
o
C.
1
H NMR (500 MHz, CDCl3) H ppm: 8,75 (1H, d, J=8,0 Hz, H-1);
8,34 (1H, dd, J = 1,0, 8,0 Hz, H-4); 7,76 (1H, dt, J = 1,0, 8,0 Hz, H-2); 7,72
(1H, d, J = 7,5 Hz, H-7); 7,66 (1H, dd, J = 1,0; 7,0 Hz, H-10); 7,50 (1H, dt, J
= 1,0; 8,0 Hz, H-3); 7,48 (1H, dt, J = 1,0, 7,5 Hz, H-8); 7,42 (1H, t, J = 7,0
Hz, H-9); 5,16 (1H, dd, J = 6,0; 14,0 Hz, Ha-1); 4,91-4,81 (2H, m, Ha-1, H-
2); 4,00 (1H, dd, J=4,5; 11,0 Hz, Ha-3 ); 3,91 (1H, dd, J = 6,0; 11,0 Hz, H b-
3).
13
C NMR (125 MHz, CDCl3& MeOD) c ppm: 190,46 (C-11); 163,68
(C-5); 155,12 (C-15); 137,05 (C-16); 134,83 (C-17); 134,57 (C-2); 133,28 (C-
8); 132,31 (C-13); 131,09 (C-9); 128,56 (C-4); 127,59 (C-3); 123,76 (C-1);
123,46 (C-14) 123,30 (C-7); 122,82 (C-10); 109,26 (C-12); 49,21 (C-2);
48,08 (C-1); 34,81 (C-3).
IR (KBr): 3070; 2933; 2850; 1741; 1691; 1660; 1606; 1573; 1546;
1498; 1417; 1377; 1313; 1190; 1068; 960; 978; 748; 713; 696; 526 cm-1.
* D liu X-ray n tinh th ca cc hp cht 171 v 172.
- Hp cht 171:
71
Hnh 2.3.1. Cu trc X-ray n tinh th ca hp cht 171
Bng 2.3.1. di cc lin kt trong hp cht 171
Nguyn t Nguyn t di (0A) Nguyn t Nguyn t di (0A)
Br(1) C(1) 1.961(19) C(5) C(14) 1.373(2)
O (2) C(2) 1.426(2) C(5) C(6) 1.504(3)
O(22) C(21) 1.230(2) C(19) C(20) 1.410(3)
O(13) C(12) 1.224(2) C(19) C(18) 1.384(3)
(4) (3) (8) (9)
N C 1.472(2) C C 1.380(3)
N (4) C(21) 1.412(2) C(15) C(20) 1.408(3)
N (4) C(5) 1.371(2) C(15) C(14) 1.441(3)
C(3) C(2) 1.540(3) C(15) C(16) 1.413(3)
C(2) C(1) 1.507(3) C(11) C(10) 1.381(3)
C(21) C(20) 1.463(3) C(11) C(6) 1.406(3)
C(7) C(8) 1.404(3) C(9) C(10) 1.402(3)
(7) (6) (17) (18)
C C 1.386(3) C C 1.395(3)
C(12) C(11) 1.495(3) C(17) C(16) 1.377(3)
C(12) C(14) 1.470(3)
72
Bng 2.3.2. Cc gc lin kt trong hp cht 171
73
* Hp cht 172:
74
Bng 2.3.4. Cc gc lin kt trong hp cht 172
75
2.3.2. Tng hp cc indenoisoquinolin 173 vi cc nhm th vng no.
Ha tan hon ton hn hp gm 171 (50 mg; 0,13 mmol) trong 3ml
Axeton trong khong 5 pht, sau b sung morpholin (17 mg; 0,195 mmol)
v K2CO3 (36 mg; 0,26mmol) vo hn hp trn. Hn hp c khuy v duy
tr nhit 60 oC trong 28h. Kt thc phn ng, quay kh c ui dung
mi, sau chit hn hp bng CH2Cl2, lm kh bng Na2SO 4, quay kh thu
c sn phm th. Sn phm th c lm sch bng sc k ct silica gel
vi h dung mi ra gii hexan/EtOAc (1:9) thu c sn phm 173a (37 mg)
vi hiu sut phn ng 73%.
Hp cht 173a l cht rn c mu vng chanh, c nhit nng chy
227-228 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,70 (1H, d, J = 8,0 Hz, H-1);
8,30 (1H, d, J = 8,0 Hz, H-4); 7,93 (1H, d, J = 7,5 Hz, H-7); 7,72 (1H, t, J =
1,0, 8,0 Hz, H-2); 7,61 (1H, d, J = 7,0 Hz, H-10); 7,45 (1H, dt, J = 1,0, 8,0
Hz, H-3); 7,44 (1H, dt, J = 1,0, 7,5 Hz, H-8); 7,37 (1H, t, J= 7,5 Hz, H-9);
4,75 (1H, dd, J = 5,0, 14,5 Hz, Ha-1); 4,51 (1H, dd, J = 6,5, 14,5 Hz, H b-1);
4,20 (1H, m, H-2); 3,79-3,68 (4H, m, H-3+H-5); 2,67-2,60 (4H, H-2+H-
6); 2,51-2,49 (2H, m, 2H-3).
13
C NMR (125 MHz, CDCl3& MeOD) c ppm: 190,65 (C-11); 164,38
(C-5); 156,10 (C-15); 137,53 (C-16); 135,04 (C-17); 134,10 (C-2); 133,14 (C-
76
8); 132,41 (C-13); 130,90 (C-9); 128,42 (C-4); 127,27 (C-3); 123,71 (C-1);
123,60 (C-14) 123,31 (C-7); 123,14 (C-10); 108,94 (C-12); 67,03 (C-3+C-
5); 66,60 (C-2) 62,77 (C-3); 53,88 (C-2+C-6) 48,69 (C-1).
IR (KBr): 3444; 3080; 2947; 2848; 2808; 1734; 1685; 1639; 1608;
1548; 1502; 1456; 1411; 1261; 1112; 1008; 964; 864; 763 cm-1.
2.3.2.2. Tng hp cht 6-(2-hydroxy-3-(4-Metylpiperidin-1-yl)propyl)-
5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion (173b).
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung 4-metylpiperidin (19,3 mg; 0,195 mmol) v
K 2CO 3 (36 mg; 0,26 mmol) vo hn hp trn. Hn hp c khuy v duy tr
nhit 60 oC trong 26h. Kt thc phn ng, quay kh c ui dung mi,
sau hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi
CH2Cl2 (310ml), lm kh bng Na2SO4, quay kh thu c sn phm th.
Sn phm th c lm sch bng sc k ct silica gel vi h dung mi ra
gii hexan/EtOAc (2:8) thu c sn phm 173b (40,8 mg) vi hiu sut phn
ng 78%.
Hp cht 173b l cht rn c mu vang chanh, c nhit nng chy
169-170 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 1H NMR (500 MHz, CDCl3) H
ppm: 8,72 (1H, d, J = 8,0 Hz, H-1); 8,32 (1H, dd, J = 0,5; 8,0 Hz, H-4); 7,98
(1H, d, J = 7,5 Hz, H-7); 7,72 (1H, dt, J = 1,0, 8,0 Hz, H-2); 7,62 (1H, dd, J
=1,0, 7,0 Hz, H-10); 7,42-7,47 (2H, m, H-3; H-8); 7,38 (1H, t, J = 7,0 Hz, H-
9); 4,76 (1H, dd, J = 5,0; 11,5 Hz, Ha-1); 4,50 (1H, dd, J = 5,5; 14,0 Hz, H b-
77
1); 4,19-4,18 (1H, m, H-2); 2,90 (2H, t, J = 11,5 Hz, H a-2+ Ha-6); 2,59-
2,63 (2H, m, 2H-3); 2,33 (1H, t, J = 11,5 Hz, H b-2); 2,04 (1H, t, J = 11,5
Hz, Hb-6); 1,65 (2H, m, Ha-3+ H a-5); 1,39 (1H, m, H-4); 1,17-1,32
(2H, m, Hb-3+ Hb-5); 0,93 (3H, d, J = 6,5 Hz, CH3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,75 (C-11); 164,42 (C-5);
156,23 (C-15); 137,54 (C-16); 135,05 (C-17); 134,06 (C-2); 133,26 (C-8);
132,46 (C-13); 130,86 (C-9); 128,43 (C-4); 127,21 (C-3); 123,96 (C-1);
123,59 (C-14) 123,34 (C-7); 123,08 (C-10); 108,90 (C-12); 66,90 (C-2)
62,58 (C-3); 55,59 (C-6); 53,18 (C-2); 48,93 (C-1) ; 34,46 (C-3); 34,20
(C-5); 30,48 (C-4); 21,79 (CH3).
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung piperidin (16,6 mg; 0,195 mmol) v K2CO3
(36 mg; 0,26 mmol) vo hn hp trn. Hn hp c khuy v duy tr nhit
60 oC trong 23h. Kt thc phn ng, quay kh c ui dung mi, sau
hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH 2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (15:85) thu c sn phm 173c (38,3 mg) vi hiu sut phn
ng 76%.
78
Hp cht 173c l cht rn c mu vng chanh, c nhit nng chy
229-230 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,73 (1H, d, J = 8,0 Hz, H-1);
8,31(1H, dd, J = 0,5, 8,0Hz, H-4); 7,95 (1H, d, J = 8,0 Hz, H-7); 7,74 (1H, dt,
J = 1,0, 8,0 Hz, H-2); 7,63 (1H, d, J = 7,0 Hz, H-10); 7,48 (1H, dt, J = 1,0,
8,0 Hz, H-3); 7,46-7,50 (2H, m, H-3; H-8); 7,38 (1H, t, J = 7,5 Hz, H-9); 4,83
(1H, dd, J = 6,0; 14,0 Hz, H a-1); 4,45 (1H, dd, J=5,5; 14,5 Hz, H b-1); 4,35-
4,32 (1H, m, H-2); 2,90 (1H, dd, J= 3,5; 13,0 Hz, Ha-3); 2,79-2,74 (5H, m,
H b-3+ 2H-2+ 2H-6); 1,73-1,67 (4H, m, H-3+H-5); 1,52-1,50 (2H, m, H-
4).
13
C NMR (125 MHz, CDCl3) c ppm: 190,75 (C-11); 164,20 (C-5);
156,16(C-15); 137,33 (C-16); 134,93 (C-17); 134,11 (C-2); 133,51 (C-8);
132,49 (C-13); 130,92 (C-9); 128,41 (C-4); 127,23 (C-3); 123,85 (C-1);
123,65 (C-14) 123,29 (C-7); 123,12 (C-10); 108,93 (C-12); 66,33 (C-2)
62,57 (C-3); 54,85 (C-2+C-6); 48,84 (C-1) ; 24,52 (C-3+C-5); 23,24
(C-4).
IR (KBr):3415; 2935; 2848; 1689; 1662; 1639; 1606; 1544; 1502; 1454;
1406; 1340; 1315; 1261; 1197; 1111; 1091; 1020; 968; 754 cm-1.
2.3.2.4. Tng hp 6-(2-hydroxy-3-(pyrrolidin-1-yl)propyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (173d)
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung pyrrolidin (13,85 mg; 0,195 mmol) v K2CO3
(36 mg; 0,26 mmol) vo hn hp trn. Hn hp c khuy v duy tr nhit
79
60 oC trong 20h. Kt thc phn ng, quay kh c ui dung mi, sau
hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH 2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
EtOAc/MeOH (9:1) thu c sn phm 173d (33,1 mg) vi hiu sut phn
ng 68%.
Hp cht 173d l cht rn c mu vng chanh, c nhit nng chy
124-125 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,41 (1H, d, J = 8,0 Hz, H-1); 8,09
(1H, d, J = 8,0 Hz, H-4); 7,78 (1H, d, J = 7,5 Hz, H-7); 7,58 (1H, dt, J = 1,0;
8,0 Hz, H-2); 7,41 (1H, dt, J = 1,5; 8,0 Hz, H-3); 7,36 (1H, dt, J=1,0; 7,5 Hz,
H-8); 7,31 (1H, t, J = 8,0 Hz, H-9); 4,58 (1H, dd, J= 4,5; 14,0 Hz, Ha-1);
4,39-4,31 (2H, m, Ha-1+H-2); 3,15-3,12 (2H, m, 2H-3); 3,08-3,04 (4H, m,
H-2+H-5); 1,96-1,92 (4H, m, H-3+H-4).
13
C NMR (125 MHz, CDCl3) c ppm: 191,8 (C-11); 165,1 (C-5); 157,8
(C-15); 138,4 (C-16); 135,8 (C-17); 134,9 (C-2); 134,4 (C-8); 133,4 (C-13);
131,9 (C-9); 129,0 (C-4); 128,1 (C-3); 125,4 (C-1); 124,3 (C-14) 124,1 (C-7);
123,5 (C-10); 109,5 (C-12); 67,7 (C-2); 60,3 (C-3); 55,6 (C-2+C-5);
49,7 (C-1) ; 24,1 (C-3+C-4).
IR (KBr): 3443; 3195; 2954; 2880; 1696; 1662; 1606; 1501; 1422;
1312; 1197; 1067; 9656; 867; 757 cm-1.
80
10
9
O
11
17 8
1
12 16
2 7
13 15 OH
14 N H
3 HN N
6
4 5
1' 3' CN
O
173e (H= 65%) NH
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml DMF trong
khong 5 pht, sau b sung 2-xyanoguanidin (16,38 mg; 0,195 mmol) v
K 2CO 3 (36 mg; 0,26 mmol) vo hn hp trn. Hn hp c khuy v duy tr
nhit 60 oC trong 30h. Kt thc phn ng, hn hp sn phm c thm
30ml nc v chit 3 ln vi dung mi CH2Cl2 (310ml), lm kh bng
Na2SO4, quay kh thu c sn phm th. Sn phm th c lm sch bng
sc k ct silica gel vi h dung mi ra gii EtOAc/MeOH (9:1) thu c
sn phm 173e (32,7 mg) vi hiu sut phn ng 65%.
Hp cht 173e l cht rn c mu cam, c nhit nng chy 202-
203 oC.
1
HNMR (CDCl3, 500 MHz) 8,35 (1H, d, J = 8,5 Hz, H-1); 7,96 (1H,
d, J = 8,5Hz, H-4); 7,65 (1H, d, J = 7,5 Hz, H-7); 7,42 (1H, t, J = 8,5 Hz, H-
2); 7,25 (1H, d, J = 7,0 Hz, H-10); 7,14-7,18 (2H, m, H-3; H-8); 7,15 (1H, d,
J = 7,5 Hz, H-9); 7,08 (1H, t, J = 7,5 Hz, H-9); 4,44 (1H, dd, J= 5,0,14,5 Hz,
H a-1); 4,30 (1H, dd, J= 8,0, 14,5 Hz, Hb-1); 3,90-3,86 (1H, m, H-2); 3,49-
3,43 (2H, m, 2H-3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,84 (C-11); 164,13 (C-5;
C=NH); 156,28 (C-15); 136,99 (C-16); 134,39 (C-17); 133,62 (C-2); 133,04
(C-8); 132,00 (C-13); 130,43 (C-9); 127,71 (C-4); 126,74 (C-3); 123,836 (C-
1); 122,85 (C-14) 122,70 (C-7); 122,40 (C-10; CN); 108,44 (C-12); 69,76 (C-
2); 63,60 (C-3); 46,89 (C-1) ;
81
IR (KBr): 3377; 3278; 3059; 2949; 2885; 2519; 2434; 1757; 1699;
1647; 1608; 1573; 1548; 1498; 1454; 1419; 1375; 1313; 1261; 1199; 1174;
1076; 875; 835 cm-1
ESI-MS: m/z 386,6 [M]+
2.3.3.2. Tng hp cht 6-(3-azido-2-hydroxypropyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (173f)
Ha tan hon ton hn hp gm 171 (200 mg; 0,52 mmol) trong 3ml
DMF, sau b sung NaN3 (101 mg; 1,56 mmol) vo hn hp trn. Hn hp
c khuy v duy tr nhit 60 oC trong 6h. Kt thc phn ng, hn hp
sn phm c thm 40ml nc v chit 3 ln vi dung mi CH 2Cl2
(320ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (6:4) thu c sn phm 173f (146 mg) vi hiu sut phn ng
81%.
Hp cht 173f l cht rn c mu tm, c nhit nng chy 161-
162 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,56 (1H, d, J = 8,5 Hz, H-1); 8,23
(1H, d, J = 8,0 Hz, H-4); 7,76 (1H, d, J = 7,5 Hz, H-7); 7,64-7,68 (1H, m, H-
2); 7,53 (1H, d, J = 7,5 Hz, H-10); 7,39-7,43 (2H, m, H-3; H-8); 7,33 (1H, d,
J = 7,5 Hz, H-9); 4,62 (2H, d, J = 4,5 Hz, H-1); 4,37 (1H, m, H-2); 3,58-
3,71 (2H, m, H-3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,83 (C-11); 164,56 (C-5);
156,19 (C-15); 137,06 (C-16); 134,49 (C-17); 133,89 (C-2); 132,21 (C-8);
82
132,05 (C-13); 130,70 (C-9); 127,91 (C-4); 127,00 (C-3); 123,73 (C-1);
123,12 (C-14); 122,80 (C-7); 122,76 (C-10); 108,67 (C-12); 68,56 (C-2);
54,72 (C-3); 47,95 (C-1).
IR (KBr): 3363; 3126; 2971; 2865; 2082; 2022; 1864; 1699; 1660;
1496; 1418; 1313; 1095; 960; 756 cm-1.
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung 1-Boc-piperazin (46,8 mg; 0,195 mmol) v
K 2CO 3 (36 mg; 0,26 mmol) vo hn hp trn. Hn hp c khuy v duy tr
nhit 60 oC trong 25h. Kt thc phn ng, quay kh c ui dung mi,
sau hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi
CH2Cl2 (310ml), lm kh bng Na2SO4, quay kh thu c sn phm th.
Sn phm th c lm sch bng sc k ct silica gel vi h dung mi ra
gii hexan/EtOAc (4:6) thu c sn phm 173g(42 mg) vi hiu sut phn
ng 66%.
Hp cht 173g l cht rn c mu cam, c nhit nng chy 203-
204 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,70 (1H, d, J = 8,5 Hz, H-1);
8,30 (1H, d, J = 8,0 Hz, H-4); 7,92 (1H, d, J= 7,5 Hz, H-7); 7,71 (1H, t, J =
8,0 Hz, H-2); 7,60 (1H, d, J = 7,0 Hz, H-10); 7,42-7,47 (2H, m, H-3+H-8);
83
7,37 (1H, t, J = 7,5 Hz, H-9); 4,75 (1H, dd, J = 5,0; 14,5 Hz, Ha-1); 4,52
(1H, dd, J = 7,0; 14,5 Hz, H b-1); 4,22-4,16 (1H, m, H-2); 3,43-3,39 (4H, m,
H-3+H-5); 2,65 (2H, d, J = 7,0 Hz, 2H-3); 2,60-2,58 (1H, m, 2H-2); 2,46-
2,42 (1H, m, 2H-6); 1,45 (9H, s, 3CH3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,6 (C-11); 164,3 (C-5); 156,0
(C-15); 154,6 (NCOOC(CH3)3); 137,5 (C-16); 135,0 (C-17); 134,1 (C-2);
133,1 (C-8); 132,4 (C-13); 130,9 (C-9); 128,4 (C-4); 127,2 (C-3); 123,7 (C-
1); 123,6 (C-14); 123,3 (C-7); 123,1 (C-10); 108,9 (C-12); 79,8 (C(CH 3)3);
66,8 (C-2); 62,3 (C-3); 53,2 (C-piperazin); 48,6 (C-1); 28,4 (3CH 3).
IR (KBr): 3557; 3045; 1764; 1699; 1634; 1586; 1490; 1438; 1322;
1231; 1088; 892; 814; 706 cm-1.
2.3.4.2. Tng hp 6-(2-hydroxy-3-(4-metylpiperazin-1-yl)propyl)-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion (173h)
10
9
O
11
17 8
1
12 16
2 7
13 15 OH 2" 3"
14 N
3 N N CH3
6
4 5
1' 3'
O 6" 5"
173h (H=49%)
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung 1-metylpiperazin (19,5 mg; 0,195 mmol) v
K 2CO 3 (36 mg; 0,26 mmol) vo hn hp trn, Hn hp c khuy v duy tr
nhit 60 oC trong 25h. Kt thc phn ng, quay kh c ui dung mi,
sau hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi
CH2Cl2 (310ml), lm kh bng Na2SO4, quay kh thu c sn phm th,
Sn phm th c lm sch bng sc k ct silica gel vi h dung mi ra
gii hexan/EtOAc (1:1) thu c sn phm 173h (25,67 mg) vi hiu sut
phn ng 49%.
84
Hp cht 173h l cht rn c mu cam, c nhit nng chy 109-
110 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,64 (1H, d, J = 8,5 Hz, H-1);
8,26 (1H, dd, J = 1,0, 8,0 Hz, H-4); 7,82 (1H, d, J = 7,5Hz, H-7); 7,69 (1H,
dt, J = 1,0; 8,0 Hz, H-2); 7,56 (1H, dd, J = 1,0; 7,5 Hz, H-10); 7,41 (2H, dt, J
= 1,0; 8,0 Hz, H-3; H-8); 7,32 (1H, t, J = 7,5 Hz, H-9); 4,73 (1H, dd, J = 5,5;
14,0 Hz, H a-1); 4,45 (1H, dd, J = 5,5; 14,0 Hz, H b-1); 4,23-4,28 (1H, m, H-
2); 2,82-2,83 (2H, m, H-3); 2,71-2,77 (8H, m, H-piperazin); 2,37 (3H, s,
CH3).
13
C NMR (125 MHz, CDCl3) c ppm: 190,5 (C-11); 164,1 (C-5); 156,0
(C-15); 137,3 (C-16); 134,9 (C-17); 134,0 (C-2); 133,1 (C-8); 132,3 (C-13);
130,8 (C-9); 128,3 (C-4); 127,1 (C-3); 123,6 (C-1); 123,4 (C-14); 123,1 (C-
7); 123,0 (C-10); 108,8 (C-12); 66,5 (C-2); 61,7 (C-3); 53,5 (C-piperazin);
48,5 (C-1); 44,5 (CH 3).
IR (KBr): 3407; 3045; 2896; 1703; 1656; 1606; 1551; 1501; 1420;
1189; 1072; 753 cm-1.
2.3.4.3. Tng hp 6-(2-hydroxy-3-(piperazin-1-yl)propyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (173i)
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung piperazin (16,78 mg; 0,195 mmol) v K2CO3
(36 mg; 0,26 mmol) vo hn hp trn, Hn hp c khuy v duy tr nhit
60 oC trong 25h. Kt thc phn ng, quay kh c ui dung mi, sau
hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH 2Cl2
85
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th, Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (4:6) thu c sn phm 173i (30,3 mg) vi hiu sut phn ng
60%.
Hp cht 173i c dng du mu thm.
1
H NMR (500 MHz, CDCl3) H ppm: 8,55 (1H, d, J = 8,5 Hz, H-1);
8,17 (1H, d, J =8,0 Hz, H-4); 7,87 (1H, d, J = 7,5 Hz, H-7); 7,68 (1H, m, H-
2); 7,48-7,35 (4H, m, H-3; H-8; H-9; H-10); 4,72-4,60 (1H, m, Ha-1); 4,49-
4,41 (1H, m, Hb-1); 4,25-4,21 (1H, m, H-2); 3,13-3,11 (2H, m, H-3); 2,78-
2,59 (8H, m, H-piperazin).
13
C NMR (125 MHz, CDCl3) c ppm: 190,0 (C-11); 165,3 (C-5); 158,1
(C-15); 138,7 (C-16); 136,0 (C-17); 135,0 (C-2); 134,4 (C-8); 133,5 (C-13);
132,0 (C-9); 129,1 (C-4); 128,2 (C-3); 125,6 (C-1); 124,4 (C-14); 124,2 (C-
7); 123,6 (C-10); 109,4 (C-12); 67,6 (C-2); 63,1 (C-3); 54,7 (C-2+C-6);
50,1 (C-1); 45,0 (C-3+C-5).
IR (KBr): 3469; 3276; 3045; 2958; 2858; 1681; 1544; 1496; 1425;
1317; 1204; 1139; 799 cm-1.
2.3.4.4. Tng hp 6-(2-hydroxy-3-(4-tosylpiperazin-1-yl)propyl)-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion (173j)
Ha tan hon ton 171 (50 mg; 0,13 mmol) trong 3ml Axeton trong
khong 5 pht, sau b sung 1-tosylpiperazin (46,8 mg; 0,195 mmol) v
K 2CO 3 (36 mg; 0,26 mmol) vo hn hp trn, Hn hp c khuy v duy tr
nhit 60 oC trong 25h. Kt thc phn ng, quay kh c ui dung mi,
86
sau hn hp sn phm c thm 30ml nc v chit 3 ln vi dung mi
CH2Cl2 (310ml), lm kh bng Na2SO4, quay kh thu c sn phm th,
Sn phm th c lm sch bng sc k ct silica gel vi h dung mi ra
gii hexan/EtOAc (3:7) thu c sn phm 173j (31,8 mg) vi hiu sut phn
ng 45%.
Hp cht 173j l cht rn c mu , c nhit nng chy 259-260
o
C.
1
HNMR (CDCl3, 500 MHz): 8,64 (1H, d, J = 8,5 Hz, H-1); 8,26 (1H,
d, J = 8,0 Hz, H-4); 7,84 (1H, d, J = 7,5 Hz, H-7); 7,71 (1H, dt, J = 1,0, 8,5
Hz, H-2); 7,61 (2H, d, J = 8,5 Hz, H-2+H-6); 7,58 (1H, d, J = 7,5 Hz, H-
10); 7,46 (1H, dt, J=1,0, 8,0 Hz, H-3); 7,38 (2H, d, J = 8,0 Hz, H-3+H-
5); 7,33 (1H, t, J = 7,5 Hz, H-8); 7,20 (1H, t, J =7,5 Hz, H-9); 4,70 (1H,
dd, J=5,0; 14,5 Hz, H a-1); 4,47 (1H, dd, J=7,5; 14,5 Hz, H b-1); 4,23-
4,11(1H, m, H-2); 3,70-3,59 (5H, m, OH+2H-3+2H-5); 2,69-2,59 (6H, m,
2H-3+2H-2+2H-6); 2,48 (3H, s, CH3).
13
C NMR (125 MHz, DMSO) c ppm: 190,96 (C-11); 162,86 (C-5);
157,44 (C-15);143,74 (C-1); 137,32 (C-16); 134,45 (C-17); 133,88 (C-2);
132,96 (C-8); 131,83 (C-4); 131,57(C-13); 130,83 (C-9); 129,89 (C-
3+C-5);128,64 (C-4); 127,91 (C-3); 127,64 (C-2+C-6); 124,99 (C-
1); 122,77 (C-14); 122,39 (C-7); 122,17 (C-10); 106,75 (C-12); 67,41 (C-2);
61,34 (C-3); 52,68 (C-2+C-6); 48,81 (C-1); 45,93 (C-3+C-5).
IR (KBr): 3461; 3300; 3133; 2911; 1834; 1736; 1690; 1647; 1546;
1505; 1419; 1161; 1068; 807; 668 cm-1.
ESI-MS: m/z 544,1 [M+H]+
87
Ha tan hon ton 29,25 mg 1H-benzo[d]imidazol-2-thiol (0,195
mmol) v 36 mg K 2CO 3 (0,26 mmol) trong 3ml Axeton trong khong 30
pht, sau cho 50 mg 171 (0,13 mmol) vo hn hp trn, Hn hp c
khuy v duy tr nhit 60 oC trong 3h. Kt thc phn ng, quay kh c
ui dung mi, sau hn hp sn phm c thm 30ml nc v chit 3 ln
vi dung mi CH2Cl2 (310ml), lm kh bng Na2SO4, quay kh thu c
sn phm th, Sn phm th c lm sch bng sc k ct silica gel vi h
dung mi ra gii hexan/EtOAc (3:7) thu c sn phm 174a (37,69 mg) vi
hiu sut phn ng 64%.
Hp cht 174a l cht rn c mu vng chanh, c nhit nng chy
194-195 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,56 (1H, d, J = 8,5 Hz, H-1);
8,16 (1H, d, J = 8,5 Hz, H-4); 7,50 (1H, dd, J = 1,0; 7,5 Hz, H-7); 7,61 (1H, t,
J = 8,0 Hz, H-2); 7,45 (1H, dd, J = 2,0; 7,5 Hz, H-10); 7,36-7,31 (3H, m, H-
3, H-8, H-9); 7,22-7,17 (2H, m, H-4+H-7); 7,07-7,04 (2H, m, H-5+H-
6); 4,84 (1H, dd, J = 5,5; 14,0 Hz, Ha-1); 4,44 (1H, dd, J = 5,5; 14,0 Hz,
H b-1); 4,40-4,37 (1H, m, H-2); 3,49 (1H, dd, J = 4,0; 14,5 Hz, H a-3); 3,39
(1H, dd, J = 5,5; 14,5 Hz, Hb-3).
13
C NMR (125 MHz, CDCl3) c ppm:191,02 (C-11); 164,14 (C-5);
156,31 (C-15); 150,73 (C-1); 137,16 (C-16); 134,59 (C-17); 133,96 (C-2);
133,28 (C-8); 132,26 (C-13); 130,69 (C-9); 128,04 (C-4); 127,89 (C-3+C-
8+C-3); 123,78 (C-1); 123,27 (C-14); 122,99 (C-7); 122,80 (C-10); 122,15
(C-4 7); 108,79 (C-12); 69,70 (C-2); 48,10 (C-1); 37,07 (C-3).
88
IR (KBr): 3583; 3079; 2924; 2861; 1664; 1603; 1540; 1426; 1314;
1188; 1079; 963; 745 cm-1.
ESI-MS: m/z 453,9 [M+H]+
2.3.5.2. Tng hp 6-(2-hydroxy-3-((5-methoxy-1H-
benzo[d]imidazolyl)thio)propyl)-5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion
(174b)
89
CH3); 3,48 (1H, dd, J = 4,0; 14,5 Hz, H a-3); 3,38 (1H, dd, J=5,5; 14,5 Hz,
H b-3).
13
C NMR (125 MHz, CDCl3) c ppm:191,02 (C-11); 164,16 (C-5);
156,31 (C-15); 156,09 (C-4); 137,16 (C-16); 134,64 (C-17); 134,01 (C-2);
133,27 (C-8); 132,31 (C-13); 130,18 (C-9); 128,08 (C-4; C-8); 127,30 (C-
3); 127,12 (C-6; C-7); 123,81 (C-1); 123,33 (C-14); 123,03 (C-7); 122,86
(C-10); 111,48 (C-5); 108,85 (C-12); 69,79 (C-2); 55,62 (OCH3); 48,23
(C-1); 37,36 (C-3).
IR (KBr): 3380; 3093; 2874; 1702; 1664; 1594; 1484; 1434; 1153;
1066; 822; 746; 647 cm -1.
ESI-MS: m/z 483,9 [M+H]+
2.4. Tng hp cc indenoisoquinolin i t 6-(2,3-ihydroxypropyl)-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion.
2.4.1. Tng hp cht 6-(2,3-ihydroxypropyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (175).
90
Hp cht 175 l cht rn c mu vng sng, c nhit nng chy 209-
211 oC.
1
H NMR (500 MHz, CDCl3 & MeOD) H ppm: 8,63 (1H, d, J = 8,0
Hz, H-1); 8,24 (1H, d, J = 8,0 Hz, H-4); 7,80 (1H, d, J = 7,5 Hz, H-7); 7,67
(1H, t, J = 8,0 Hz, H-2); 7,54 (1H, d, J = 7,0 Hz, H-10); 7,38-7,42 (2H, m, H-
3; H-8); 7,32 (1H, t, J = 7,0 Hz, H-9); 4,73 (1H, dd, J = 6,0; 14,5 Hz, H a-1);
4,46 (1H, dd, J = 5,5; 14,5 Hz, Hb-1); 4,06-4,09 (1H, m, H-2); 3,71 (1H, dd,
J = 4,0; 12,0 Hz, Ha-3); 3,63 (1H, dd, J = 4,0; 12,0 Hz, H b-3).
13
C NMR (125 MHz, CDCl3) c ppm:190,90 (C-11); 164,67 (C-5);
156,96 (C-15); 137,10(C-16); 134,66 (C-17); 134,19 (C-2); 133,47 (C-8);
132,32 (C-13); 130,91 (C-9); 128,19 (C-4); 127,29 (C-3); 123,61 (C-1);
123,39 (C-14); 123,11 (C-7); 122,97 (C-10); 109,07 (C-12); 70,29 (C-2);
63,53 (C-3); 46,80 (C-1).
IR (KBr): 3545; 3365; 3154; 3048; 2930; 2868; 1779; 1732; 1700;
1640; 1500; 1420; 1315; 1193; 1075; 960; 876; 756 cm-1.
Ha tan hon ton hn hp 175 (50 mg; 0,16 mmol) v Et3N (49 mg;
0,48 mmol) trong 5ml CH2Cl2, sau b sung MsCl (21,9 mg; 0,192 mmol)
vo hn hp trn. Hn hp c khuy v duy tr nhit 0 oC trong 4h.
Kt thc phn ng, quay kh c ui dung mi, sau chit hn hp bng
EtOAc, lm kh bng Na2SO 4, quay kh thu c sn phm th. Sn phm
91
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (3:7) thu c sn phm 176a (37 mg) vi hiu sut phn ng
58%.
Hp cht 176a l cht rn c mu tm, c nhit nng chy 127-
128 oC.
1
H NMR (500 MHz, DMSO) H ppm: 8,60 (1H, d, J = 8,0 Hz, H-1);
8,22 (1H, d, J = 8,0 Hz, H-4); 7,96 (1H, d, J = 7,5 Hz, H-7); 7,83 (1H, dt, J=
1,0, 8,0 Hz, H-2); 7,57-7,52 (3H, m, H-3; H-8; H-10); 7,48 (1H, t, J = 7,5 Hz,
H-9); 5,73 (1H, d, J = 5,5 Hz, OH); 4,63 (1H, dd, J = 4,5; 14,5 Hz, Ha-1);
4,50 (1H, dd, J = 8,5; 14,5Hz, H b-1); 4,41 (1H, dd, J = 4,0; 10,5 Hz, H a-3);
4,35 (1H, dd, J = 5,5; 10,5 Hz, H b-3); 4,29-4,26 (1H, m, H-2); 3,24 (3H, s,
CH3).
13
C NMR (125 MHz, CDCl3 & DMSO) c ppm:190,11 (C-11); 162,79
(C-5); 157,45 (C-15); 137,20 (C-16); 134,32 (C-17); 134,03 (C-2); 133,40 (C-
8); 131,91 (C-13); 130,99 (C-9); 128,00 (C-4); 127,02 (C-3); 124,89 (C-1);
122,80 (C-14); 122,51 (C-7); 122,24 (C-10); 107,08 (C-12); 71,89 (C-2);
66,19 (C-3); 46,73 (C-1); 36,8 (CH3).
IR (KBr): 3430; 3251; 2911; 1744; 1710; 1654; 1574; 1530; 1408;
1173; 1122; 1049; 861; 786; 665 cm-1.
2.4.2.2. Tng hp cht 3-(5,11-ioxo-5,11-ihydro-6H-indeno[1,2-
c]isoquinolin-6-yl)-2-hydroxypropyl 4-Metylbenzenesunfonat (176b)
Ha tan hon ton hn hp 175 (50 mg; 0,16 mmol) v Et3N (49 mg;
0,48 mmol) trong 5ml CH2Cl2, sau b sung TsCl (36,5 mg; 0,192 mmol)
92
vo hn hp trn. Hn hp c khuy v duy tr nhit 0 oC trong 4h.
Kt thc phn ng, quay kh c ui dung mi, sau hn hp sn phm
c thm 30ml nc v chit 3 ln vi dung mi CH2Cl2 (310ml), lm kh
bng Na2SO 4, quay kh thu c sn phm th. Sn phm th c lm sch
bng sc k ct silica gel vi h dung mi ra gii hexan/EtOAc (3:7) thu
c sn phm 176b (41 mg) vi hiu sut phn ng 54%.
Hp cht 176b l cht rn c mu tm, c nhit nng chy 129-
130oC.
1
H NMR (500 MHz, DMSO) H ppm; 8,60 (1H, d, J = 8,0 Hz, H-1);
8,22 (1H, d, J = 8,0 Hz, H-4); 8,05 (1H, d, J = 7,5 Hz, H-7); 7,82 (2H, d, J =
7,0 Hz, H-2+H-6); 7,78 (1H, t, J = 8,0 Hz, H-2); 7,50-7,55 (4H, m, H-3;
H-8; H-9; H-10); 7,47 (2H, d, J = 8,0 Hz, H-3+H-5); 4,60-4,49 (2H, m,
2H-1); 4,21-4,15 (2H, m, 2H-3); 4,02-3,99 (1H, m, H-2); 2,39 (3H, s, CH 3).
13
C NMR (125 MHz, CDCl3 & DMSO) c ppm:190,1 (C-11); 162,8 (C-
5); 157,6 (C-15); 145,7 (C-1); 137,5 (C-4);137,3 (C-16); 134,4 (C-17);
133,9 (C-2); 133,3 (C-8); 131,9 (C-13); 130,9 (C-9); 129,7 (C-4); 127,9 (C-3;
C-3; C-5); 126,9 (C-1); 125,1 (C-2; C-6); 122,8 (C-14); 122,4 (C-7);
122,1 (C-10); 106,8 (C-12); 69,0 (C-2); 63,9 (C-3); 47,6 (C-1); 20,7 (CH3).
IR (KBr): 3413; 3239; 3064; 2921; 2877; 1729; 1691; 1648; 1538;
1504; 1411; 1632; 1197; 1122; 1034; 763; 769 cm-1.
93
Ha tan hon ton hn hp 175 (50 mg; 0,16 mmol) v Et3N (49 mg;
0,48 mmol) trong 5ml CH 2Cl2, sau b sung isobutyric anhydrit (30,3 mg;
0,192 mmol) vo hn hp trn. Hn hp c khuy v duy tr nhit
phng trong 2h. Kt thc phn ng, quay kh c ui dung mi, sau hn
hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (8:2) thu c sn phm 176a (40,7 mg) vi hiu sut phn ng
65%.
Hp cht 176a l cht rn c mu tm, c nhit nng chy 174-
175 oC.
1
H NMR (500 MHz, CDCl3) H ppm: 8,57 (1H, d, J = 8,0 Hz, H-1);
8,22 (1H, d, J = 8,0 Hz, H-4); 7,72 (1H, d, J = 7,5 Hz, H-7); 7,64 (1H, dt, J
= 1,5, 7,5 Hz, H-2); 7,52 (1H, dd, J= 1,0, 7,0 Hz, H-10); 7,36-7,40 (2H, m,
H-3; H-8 ); 7,32 (1H, t, J= 7,0 Hz, H-9); 4,67- 4,60 (2H, m, 2H-1); 4,50-4,45
(1H, m, H-2); 4,37 (2H, d, J= 5,0 Hz; 2H-3); 3,57 (1H, s, OH); 2,71-2,65
(1H, m, CH); 1,25 (6H, dd, J = 2,0; 7,0 Hz, 2CH 3).
13
C NMR (125 MHz, CDCl3) c ppm:190,54 (C-11); 177,14 (C-5);
164,66 (C-5); 155,85 (C-15); 137,29 (C-16); 134,84 (C-17); 134,15 (C-2);
133,09 (C-8); 132,24 (C-13); 130,95 (C-9); 128,29 (C-4); 127,27 (C-3);
123,48 (C-1); 123,21 (C-14; C-7); 123,12 (C-10); 109,05 (C-12); 69,22 (C-
2); 66,45 (C-3); 47,95 (C-1); 34,05 (C-6); 19,02 (C-7+C-8).
IR (KBr): 3379; 3249; 3007; 2975; 2852; 1733; 1656; 1618; 1479;
1420; 1259; 1155; 971; 760 cm-1.
2.4.3.2. Tng hp cht 3-(5,11-ioxo-5,11-ihydro-6H-indeno[1,2-
c]isoquinolin-6-yl)-2-hydroxypropyl acetat (177b)
94
Ha tan hon ton hn hp 175 (50 mg; 0,16 mmol) v Et3N (49 mg;
0,48 mmol) trong 5ml CH2Cl2, sau b sung Axetic anhydrit (19,6 mg;
0,192 mmol) vo hn hp trn. Hn hp c khuy v duy tr nhit
phng trong 2h. Kt thc phn ng, quay kh c ui dung mi, sau hn
hp sn phm c thm 30ml nc v chit 3 ln vi dung mi CH2Cl2
(310ml), lm kh bng Na2SO4, quay kh thu c sn phm th. Sn phm
th c lm sch bng sc k ct silica gel vi h dung mi ra gii
hexan/EtOAc (8:2) thu c sn phm 177b (36 mg) vi hiu sut phn ng
62%.
Hp cht 177b l cht rn c mu tm, c nhit nng chy 153-
154 oC.
1
HNMR (CDCl3, 500 MHz) 8,61 (1H, d, J = 8,0 Hz, H-1); 8,25 (1H,
dd, J = 1,0; 8,0 Hz, H-4); 7,72 (1H, d, J = 7,5 Hz, H-7); 7,67 (1H, dt, J = 1,5;
8,0 Hz, H-2); 7,55 (1H, dd, J = 1,0; 7,5 Hz, H-10); 7,42-7,39 (2H, m, H-3; H-
8); 7,34 (1H, t, J = 7,5 Hz, H-9); 4,68-4,64 (2H, m, 2H-1); 4,47-4,43 (1H, m,
H-2); 4,39-4,33 (2H, m, 2H-3); 3,52 (1H, d, J= 5,5 Hz, OH); 2,17 (3H, s,
CH3).
13
C NMR (125 MHz, CDCl3 ) c ppm: 190,51 (C-11); 170,89 (C-5);
164,72 (C-5); 155,77 (C-15); 137,27 (C-16); 134,85 (C-17); 134,19 (C-2);
133,11 (C-8); 132,27 (C-13); 130,98 (C-9); 128,33 (C-4); 127,33 (C-3);
123,51 (C-1); 123,23 (C-14; C-7); 123,13 (C-10); 109,14 (C-12); 69,18 (C-
2); 66,46 (C-3); 47,92 (C-1); 20,81 (C-6).
IR (KBr): 3437, 3124, 2943, 2868; 1735; 1696; 1635; 1548; 1429;
1385; 1225; 1035; 850; 753 cm-1.
95
2.5. Hot tnh gy c t bo ung th ca cc hp cht
Cc hp cht indenoisoquinolin tng hp c cho tin hnh th hot
tnh gy c t bo trn cc dng t bo ung th c ngun gc t Bo tng
ging chun Hoa k (ATCC) gm: ung th biu m biu b ming KB
(Human epidermic carcinoma; CCL -17 TM), ung th gan Hep G2
(Hepatocellular carcinoma; HB - 8065TM) bng phng php MTT (3-(4,5-
dimethylthiazol-2 - yl )- 2, 5 - diphenyltetrazolium) [73] trn m hnh th
c t bo in vitro c Vin Ung th Quc gia Hoa k (NCI) xc nhn l
php th c t bo chun nhm sng lc, pht hin cc cht c kh nng
km hm s pht trin hoc dit t bo ung th iu kin in vitro.
Cc dng t bo ung th nghin cu c nui cy trong cc mi
trng nui cy ph hp c b sung thm 10% huyt thanh phi b (FBS) v
cc thnh phn cn thit khc iu kin tiu chun (5% CO 2; 37oC; m
98%; v trng tuyt i). Ty thuc vo c tnh ca tng dng t bo khc
nhau m la chn thi gian cy ph hp.
Th c t bo c thc hin: 200l dung dch t bo c pha long
nng 3 x 104 t bo/ml vo mi ging (a 96 ging) trong mi trng
RPMI 1640 cho cc dng t bo HepG2, MCF7, KB; mi trng DMEM cho
LU-1, mu th c x l vi t bo cc nng pha long khc nhau sao
cho t n nng cui cng l 128 g/ml; 32g/ml; 8g/ml; 2g/ml v
0,5g/ml. mu th iu kin: 37 oC, 5% CO 2, thi gian 3 ngy, ging
iu khin gm 200 l dung dch t bo 3x104 t bo/ml, 37 oC, 5% CO2,
thi gian 3 ngy, thm 50 l MTT (1 mg/ml pha trong mi trng nui cy
khng huyt thanh), 37 oC, 4 gi, loi b mi trng, thm 100 l DMSO
lc u v c kt qu bc sng 540 nm trn my spectrophotometter
Genios TECAN.
Phn trm km hm s pht trin ca t bo (Growth inhibition) IC50
c tnh da trn kt qu s liu phn trm km hm s pht trin ca t bo
bng phn mm my tnh table curve. Kt qu th hot tnh gy c t bo
c th hin bng 3.6.1 v bng 3.6.2.
96
CHNG 3: KT QU V THO LUN
97
ng quen thuc nh anken, ankin, axt cacboxylic, amin thc hin cc
nghin cu tip theo nhm to ra nhiu dn xut indenoisoquinolin mi c
hot tnh sinh hc l th. Trong cc indenoisoquinolin mi c trung tm phn
ng quen thuc tng hp c, lun n chn 6-allyl-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (169i) thc hin cc phn ng tng hp tip
theo v nhm chc anken c th thc hin c nhiu phn ng ha hc thun
li, ng thi nhm th allyl vng B ca indenoisoquinolin cn m bo
mc tiu ca lun n l cc nhm th a vo cch nguyn t Nit ca vng
indenoisoquinolin 3 nguyn t cacbon.
Trn c s , cng kt qu nghin cu ca cc nh khoa hc cho thy
cc nhm th vng B ti v tr nguyn t nit (N-6) l cc nhm
aminopropyl, morpholinopropyl, imdazolopropyl cho kh nng gy c t bo
rt tt, trong c 2 hp cht ang c th nghim lm sng giai on II l
Indotecan (5) v Indimitecan (6) [6,8,15,22,42,44]. Do , lun n tip tc
thit k tng hp cc indenoisoquinolin mi, bng cch a thm nhm
hydroxyl vo v tr th 2 ca nhm propyl cn v tr th 3 l cc d vng
morpholin, piperidin, pyrrolidin, piperazin, benzimidazolthio vi hy vng lm
tng kh nng tng tc ca cc nhm th vng B ca indenoisoquinolin
vi DNA v Top1 ti v tr phn ct ca topoisomerase I. Ngoi ra, vi mc
tiu l tng hp cc indenoisoquinolin mi c nhm th khc nhau cha cc
d t cch nguyn t N vng indenoisoquinolin 3 nguyn t cacbon lun n
cng thit k tng hp cc dn xut indenoisoquinolin mi t 6-(2,3-
ihydroxypropyl)-5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion (175) vi hy
vng cc cht tng hp c s cho nhiu hot tnh sinh hc l th.
98
O
O
H
+ O
OH
O O
D O D
C C
A B A H
B
N N C COOH
R O
O O R1
O
169 59 170
O O
D D
C C
A
Br
B A B
N Br N
O O
169j
172
O O O
D D D
C C C
OH OH OH
A B A B A B
N X N Br N SR
O O O
173 174
(X = NR1R2) 171
O O
O D
D D C
C C
OH OH
A B OH A B
A B N OCOR
N OSO2R N OH
O O
O
177
176
175
99
3.2. Tng hp indeno[1,2-c]isochromen-5,11-ion (59)
Bc cha kha tng hp indenoisoquinolin theo phng php m
chng ti la chn l tng hp c Indeno[1,2-c]isochromen-5,11-ion (59)
cc phn ng tng hp c tm tt s 3.2.
100
nhn indenoisoquinolin l H-8 v H-10 c tn hiu cng hng chng lp
trong khong 7,45-7,48 ppm.
101
Ngoi ra cu trc ca hp cht 59 cn c khng nh bi ph cng
13
hng t C-NMR, trn ph xut hin y tn hiu cng hng ca 16
nguyn t cacbon bao gm tn hiu ca nhm cacbonyl (C-11) ti C 189,96
ppm, nhm cacbonyl ca vng lacton ti C 170,59 ppm (C-5). Tn hiu ti C
160,81 ppm (C-15) c quy kt cho cacbon thuc vng indeno ni vi oxi
vng lacton, cng 13 tn hiu cng hng khc ti C 136,38 (C-16); 135,99
(C-17); 133,66 (C-2); 132,81(C-8); 132,67 (C-13); 131,64 (C-9); 130,87 (C-
4); 128,39 (C-3); 123,30 (C-1); 123,15 (C-14); 119,82 (C-7); 118,97 (C-10);
107,71 (C-12).
102
Hnh 3.2.4. Ph 13C-NMR gin rng ca hp cht 59
O O
O O
H
O
O OH O
O R
O O OH
O
103
3.3. Tng hp cc indenoisoquinolin trn c s ca phn ng gia
indeno[1,2-c]isochromen-5,11-ion vi cc amin bc 1.
104
3.3.1. Tng hp cc dn xut indenoisoquinolin 169 vi R l cc nhm
benzyl, phenyl.
105
dao ng ha tr ca C=O, cc nh 1699 v 1654 cm1 c trng cho dao
ng ha tr C=O lin hp. Ngoi ra, dao ng ha tr ca C=C vng thm
cng c nhn thy ti cc nh 1606, 1546, 1500 cm1, dao ng ha tr
ca ete thm C-O c nhn thy ti nh 1247 cm1.
106
nhn indenoisoquinolin l H-8, H-9 v H-10 c tn hiu cng hng chng
lp trong khong 7,26-7,36 ppm.
107
Ngoi ra cu trc ca hp cht 169a cn c khng nh bi ph cng
hng t ht nhn 13C-NMR, trn ph xut hin y tn hiu cng hng
ca 24 nguyn t cacbon bao gm tn hiu ca nhm cacbonyl (C-11) ti C
190,53 ppm, nhm cacbonyl ca vng lactam ti C 163,48 ppm (C-5). Tn
hiu ti C 156,16 ppm (C-15) c quy kt cho cacbon thuc vng indeno
ni vi nit vng lactam, tn hiu ca cacbon vng benzen ni vi nhm
metoxy cng hng ti C 159,09 ppm (C-4), tn hiu cng hng ti C 55,29
ppm c trng cho cng hng ca cacbon nhm metoxy, tn hiu ti C 47,69
ppm c quy kt cho tn hiu cng hng ca nhm CH2 ni gia vng
benzen v indenoisoquinolin cng y tn hiu ca cacbon khc cho php
khng nh cu trc hp cht 169a.
108
Cc cht ny s c th hot tnh gy c t bo trn cc dng t bo ung
th ung th biu m biu b ming (KB), ung th gan (Hep G2).
3.3.2. Tng hp cc dn xut indenoisoquinolin 169 vi R l cc d vng
thm.
Tip tc vi mc tiu tng hp indenoisoquinolin mi c nhm th khc
nhau vng B cha cc d t N, O cch nguyn t N vng B ca
indenoisoquinolin 2 n 3 nguyn t cacbon lun n tip tc thc hin
phn ng gia hp cht 59 vi cc amin bc 1 (R-NH 2) c R l cc gc d
vng thm nh 5-amino-2-metoxypyridin, pyridin-2-ylmetanamin v furan-2-
ylmetanamin thu c cc hp cht 169f , 169g, 169h vi hiu sut tng
ng l 83%, 86%, 83%.
109
(1H, td, J= 2,5; 8,0 Hz, H-3), 7,26 (1H, td, J = 2,5; 7,5 Hz, H-8), 7,10 (1H, t, J
= 0,5; 7,5 Hz, H-9), 7,01 (1H, d, J = 8,5 Hz, H-10).
110
Cu trc ca hp cht 169f cn c khng nh bi ph cng hng t
13
C-NMR, trn ph ta thy xut hin 22 tn hiu ca cacbon vi tn hiu c
trng ca nhm cacbonyl C-11 ti C 190,52 ppm, nhm cacbonyl ca amit ti
C 163,80 ppm (C-5). Tn hiu ti C 164,66 ppm c quy kt cho nhm
N=COCH 3, tn hiu cacbon ca nhm OCH3 cng hng ti C 54,19 ppm.
Cc d liu ph trn cho php khng nh cu trc ca 169f.
111
tn hiu c trng ca C=N trong vng pyridin C 149,6 ppm, xut hin tn
hiu ca nhm CH2 gn gia khung indenoisoquinolin v vng pyridin cng
hng ti C 49,6 ppm cng cc tn hiu c trng ca khung
indenoisoquinolin cho php khng nh cu trc ca 169g.
Tng t, trn ph 1H-NMR ca hp cht 169h xut hin cc tn hiu
c trng ca nhm CH2 gn gia khung indenoisoquinolin v vng Furan
cng hng ti ti H 5,72 (2H, s), xut hin tn hiu doulet ti H 6,75 (1 H, J
= 2,0; 3,5 Hz) c gn cho H-4 trong vng furan, cng cc d liu ph chi
tit trn cho php khng nh cu trc ca 169h.
Nh vy lun n tng hp c 3 dn xut ca indenoisoquinolin
vi cc nhm th vng B cha cc d t N, O cch nguyn t N vng B
ca indenoisoquinolin 2 n 3 nguyn t cacbon l hp cht 169f-h. Cc
cht ny s c th hot tnh gy c t bo trn cc dng t bo ung th
ung th biu m biu b ming (KB), ung th gan (Hep G2).
112
S 3.3.4. S tng hp indenoisoquinolin 169i-p vi R l gc hu
c mch h.
Hp cht 169i c tng hp khi cho indeno[1,2-c]isochromen-5,11-ion
(59) phn ng vi 1,1 ng lng 3-aminopropin trong dung mi CH2Cl2 ti
nhit phng trong 22 gi thu c sn phm l cht bt c mu cam, c
nhit nng chy l 226-227 oC. Trn ph 1H-NMR ca hp cht 169i, xut
hin tn hiu cng hng ca mt proton ti H 2,49 ppm (1H, s, H-3), mt
tn hiu ca nhm metylen ni vi Nit v cacbon lai ha sp ca ni ba ti H
5,28 ppm (2H, s, H-1). Cng y tn hiu cng hng ca 8 proton khung
indenoisoquinolin: Tn hiu doublet cng hng ti 8,62 ppm vi hng s
tng tc J = 8,0 Hz l c trng ca proton H-1. Tn hiu doublet vi hng
s tng tc J = 8,0 Hz ti 8,31 ppm l c trng cng hng ca proton H-4.
Cng hai tn hiu doublet cng tng ti 7,77 ppm v 7,56 ppm c quy kt
cho proton H-7 v H-10. Hai tn hiu cng hng triplet ca 2 proton bao
gm: proton v tr H-2 cng hng ti 7,70 ppm vi hng s tng tc J =
8,0 Hz, proton v tr H-9 cng hng ti 7,38 ppm vi hng s tng tc J =
7,0 Hz. Hai proton cn li ca nhn indenoisoquinolin l H-8, H-3 c tn hiu
cng hng chng lp trong khong 7,43-7,47 ppm.
113
Hnh 3.3.8. Ph 1H-NMR ca hp cht 169i
114
13
Trn ph C-NMR ca hp cht 169i xut hin y tn hiu cng
hng ca 19 nguyn t cacbon, bao gm tn hiu c trng ca khung
indenoisoquinolin nh nhm cacbonyl (C-11) ti C 189,99 ppm, nhm
cacbonyl ca vng lactam ti C 162,20 ppm (C-5), tn hiu ca cacbon thuc
vng indeno ni vi nit vng lactam ti C 156,16 ppm (C-15). Ngoi ra trn
ph cn xut hin tn hiu c trng ca cacbon ankin ni ba u mch ti C
74,32 ppm (C-3), xut hin tn hiu ca cacbon trong lin kt ba cn li ti C
78,03 ppm (C-2), xut hin tn hiu ca cacbon nhm metylen ni vi Nit
v cacbon lai ha sp ca ni ba cng hng ti C 33,94 ppm (C-1) cng cc
tn hiu c trng ca khung indenoisoquinolin cho php khng nh cu trc
ca 169i.
115
nhnh H-1 (H 5,27) v mt proton vng thm H-4 (H 8,31). iu ny cho
thy vic quy kt proton H-4 chuyn dch H 8,31 hon ton hp l, kt
qu ny cng cho thy s phng on v tr proton H-4 c chuyn dch t
trng thp nht trong cc proton khung indenoisoquinolin (H 8,61) ti liu
s tham kho s 78 v s 2 cn c xem xt li. Ngoi ra trn ph cn xut
hn tn hiu tng tc ca cacbon C-15 (C 154,94) vi proton H-1 (H 5,27)
v proton H-7 (H 7,77), s tng tc ca cacbon nhm cacbonyl C-11 (C
189,99) vi proton H-10 (H 7,56). Cc kt qu phn tch trn cng cc tn
hiu c trng trn ph 1H-NMR cho php khng nh chuyn dch ca
proton H-4 (H 8,31), H-7 (H 7,77) , H-10 (H 7,56), H-1 (H 8,56).
Ngoi cc tn hiu k trn, phn tch ph gin HMBC vng cacbon vng
thm cn thy xut hin tn hiu tng tc ca proton H-1 (H 8,56) vi C-14
(C 123,13) v C-3 (C 127,02); tng tc ca proton H-4 (H 8,31) vi C-13
116
(C 131,99) v C-2 (C 133,79); tng tc ca proton H-7 (H 7,77) vi C-17
(C 134,49) v C-9 (C 130,82); tng tc ca proton H-10 (H 7,56) vi C-16
(C 136,50) v C-8 (C 133,04). iu cho thy cc quy kt hon ton ph
hp. Cc kt qu phn tch trn, cng cc kt qu trn HSQC cho thy cc
quy kt chuyn dch proton v cacbon trn cu trc phn t hp cht 169i
hon ton chnh xc v ph hp.
117
Hnh 3.3.13. Ph HSQC gin ca hp cht 169i
118
3.3.4. Tng hp cc indenoisoquinolin 170 trn c s ca phn ng gia
indeno[1,2-c]isochromen-5,11-ion vi cc -amino axt.
Adina Ryckebusch v cc cng s nghin cu tng hp cc dn cht
ca indenoisoquinolin vi mch nhnh c tng hp l cc este v amit ca
cc axt amin khc nhau c di n t 2 n 3 cacbon v pht hin dn
cht amit vi axt amin Arginin (n = 2) v glyxin (n = 2) c hot tnh c ch
topoisomerase II cao nht [32]. Trn c s lun n cng tng hp cc
dn xut ca indenoisoquinolin 170 thng qua phn ng gia hp cht 59 vi
cc amin bc 1 l cc -amino axt nh: Glyxin, L-Valin, L-Phenyl alanin, L-
Tyrosin, 3,4-ihydroxyphenylalanin thu c cc hp cht 170a, 170b, 170c,
170d, 170e vi hiu sut tng ng l 88%, 86%, 85%, 81%, 81%.
119
Hz, Proton v tr H-7 cng hng ti 7,57 ppm vi hng s tng tc J =
6,5 Hz. Bn proton cn li ca nhn indenoisoquinolin l H-3, H-8, H-9 v H-
10 c tn hiu cng hng chng lp trong khong 7,32-7,48 ppm. Ngoi ra
trn ph 1H-NMR ca hp cht 170a xut hin tn hiu cng hng singlet
ca 2 proton 5,27 ppm c quy kt cho proton ca nhm metylen ca
13
mch nhnh glyxin gn vi nhn indenoisoquinolin. Ph C-NMR ca hp
cht 170a xut hin y tn hiu cng hng ca 18 nguyn t cacbon.
Trong tn hiu ca nhm cacbonyl xeton (C-11) cng hng ti 190,8
ppm. Nhm cacbonyl amit (C-5) cng hng ti 168,5 ppm. Nhm
cacboxylic ca mch nhnh glixin cng hng ti 170,0 ppm, tn hiu cng
hng ti 45,8 ppm c quy kt cho nhm metylin ca glixin. Kt qu phn
tch ph cng hng 1H-NMR v 13C-NMR cho php khng nh cu trc ca
indenoisoquinolin 170a.
120
Tng t, ph 1H-NMR ca hp cht 170b th hin y tn hiu cng
hng ca proton c mt trong phn t, trong vng trng thp th hin
u tn hiu cng hng 8 proton ca nhn indenoisoquinolin. Tn hiu
doublet cng hng ti 4,64 ppm vi hng s tng tc J = 7,0 Hz l c
trng ca proton H-2 ca mch nhnh valin. Tn hiu multiplet ti 2,84 ppm
l c trng ca nhm metin (H-4) lin kt vi hai nhm metyl ca mch
nhnh valin. Hai nhm metyl cng hng ti 1,13 ppm (6H, d, J = 6,5 Hz, H-
4, H-5). Kt qu phn tch trn cho php khng nh cu trc ca 170b. Hp
cht 170c v 170d cng c khng nh tng t nh ph cng hng t ht
nhn. Vng trng thp trn ph 1H-NMR ca hp 170c ngoi tn hiu cng
hng ca 8 proton c trng ca nhn indenoisoquinolin cn xut hin thm
tn hiu ca 5 proton ca phenyl. Ngoi ra trn ph 1H-NMR ca 170c cn
xut hin tn hiu multiplet ca 1 proton ti 5,33 ppm l c trng ca proton
H-2 ca mch nhnh phenylalanin. Hai proton ti v tr H-3 l mt cp
doublet-doublet ti 3,54 v 3,24 ppm vi hng s tng tc l 2,5 v 12,5 Hz.
D liu phn tch ph 1H-NMR cho php khng nh cu trc ca 170c. Ph
1
H-NMR ca 170d tng t nh ca 170c, ch c s khc bit duy nht trn
vng trng thp l tn hiu ca nhn thm th 1,4 ti 6,62 ppm (2H, d, J =
8,0 Hz, H-2 v H-6) v 6,29 ppm (2H, J = 8,0 Hz, H-3 v H-5).
Nh vy lun n tng hp c 5 dn xut mi ca indenoisoquinolin
trn c s ca phn ng gia indeno[1,2-c]isochromen-5,11-ion vi cc -
amino axt, hp cht 170a-e. Cc cht ny s c th hot tnh gy c t
bo trn cc dng t bo ung th biu m biu b ming (KB), ung th gan
(Hep G2), ng thi mch nhnh vn cn nhm chc cacboxyl cng l
c s cho cc hng nghin cu tip theo nhm to ra cc dn xut khc nhau
ca indenoisoquinolin vi hy vng tm ra nhiu hp cht c hot tnh sinh hc
l th.
121
3.4. Tng hp cc indenoisoquinolin i t 6-allyl-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion.
Nh phn tch trn vi tng thit k tng hp cc
indenoisoquinolin mi c nhm propyl vng B ng thi a thm nhm
hydroxyl vo v tr th 2 ca nhm propyl, lun n tip tc tng hp cc
indenoisoquinolin mi khi cho 6-allyl-5H-indeno[1,2-c]isoquinolin-5,11(6H)-
ion (169i) phn ng vi brom, sn phm thu c tip tc cho phn ng vi
cc hp cht d vng morpholin, piperidin, pyrrolidin, piperazin,
benzimidazolthio thu c cc indenoisoquinolin 173, 174 nh s :
O O
O
CH2Cl2/H2O (50:1)
OH + Br
0-5 oC, 12h
N Br N Br
N 2 .l Br2
0 C O 171 O 172
O 0
,7
2C H
on 1.5 .l XH
S
t
3
lK R
169j
O
e
Ax
. .l
2 .l K2CO3
2 .5
O
O
OH
OH
N S
R N X
O 174
O 173
122
proton mch nhnh vng trng cao hn. Tn hiu cng hng ca mt
proton vi hng s tng tc ln ti H 5,16 ppm ( 1H, dd, J = 6,0; 14,0 Hz)
c quy kt cho proton Ha-1 ca nhm metylen mch nhnh gn vi nhn
indenoisoquinolin, hai tn hiu doublet doublet cng hng ti H 4,00 ppm
(1H, dd, J = 4,5; 11,0 Hz) v H 3,91 ppm (1H, dd, J = 6,0; 11,0 Hz) vi
hng s tng tc ln c quy kt cho proton Ha-3 v H b-3, tn hiu ca
hai proton Hb-1v H-2 cng hng chng lp ti H 4,91-4,81 (2H, m). Tn
hiu cng hng ca 8 proton khung indenoisoquinolin cng c thy r
trn ph ti cc chuyn dch: H 8,75 ppm (1H, d, J = 8,0 Hz, H-1), H 8,34
ppm (1H, dd, J = 0,5; 8,0 Hz, H-4), H 7,76 ppm (1H, dt, J = 1,0; 8,0 Hz, H-
2), H 7,72 ppm (1H, d, J = 7,5 Hz, H-7), H 7,66 ppm (1H, d, J = 1,0; 7,0 Hz,
H-10), H 7,50 ppm (1H, dt, J = 1,0, 8,0 Hz, H-3), H 7,48 ppm (1H, dt, J =
1,0, 7,5 Hz, H-8), H 7,42 ppm (1H, t, J = 7,0 Hz, H-9).
123
Hnh 3.4.2. Ph 1H-NMR gin rng ca hp cht 172
13
Ph C-NMR ca hp cht 172 xut hin y tn hiu cng hng
ca 19 nguyn t cacbon. Trong tn hiu ca nhm cacbonyl xeton (C-11)
cng hng ti 190,46 ppm. Nhm cacbonyl amit (C-5) cng hng ti
163,68 ppm. Tn hiu ti cng hng ca cacbon ti C 49,21 ppm c quy
kt cho cacbon ca nhm (Br)CH (C-2), tn hiu ca cacbon nhm CH2 ni
vi nhn indenoisoquinolin cng hng ti C 48,08 ppm (C-1) cng tn hiu
cng hng ti C 34,81 ppm (C-3) c quy kt cho cacbon ca nhm
(Br)CH 2 . Qua cc d kin va phn tch cng cc d liu ph chi tit trn
cho php khng nh cu trc ca hp cht 172.
124
Hnh 3.4.3. Ph 13C-NMR ca hp cht 172
125
Hnh 3.4.4. M hnh cu trc phn t ca hp cht 172 theo phng
php X-ray tinh th.
126
cacbon mch nhnh cng hng ti C 68,5 ppm (C-2); C 49,2 ppm (C-1);
C 36,3 ppm (C-3).
127
Cu trc ca hp cht 171 mt ln na c khng nh bi cc d liu
X-ray crystal. Cc s liu ghi chp, tnh ton v ti u ha cho thy hp cht
171 c cng thc phn t l C19H14BrNO3, khi lng phn t l 384.22,
trong phn t ch c mt nguyn t brm xut hin thm mt nguyn t Oxi
vi di lin kt O(2) - C(2) l 1,426 0A c trng cho lin kt C-O ancol
cng cc gc lin kt O(2) - C(2)-C(3) l 108,570, O(2) - C(2)-C(1) l 113,420 v cc
d liu tng t khc ging hp cht 172 cho php khng nh cu trc ca
hp cht 171.
Hnh 3.4.7. M hnh cu trc phn t ca hp cht 171 theo phng php X-
ray tinh th.
128
3.4.1. Tng hp cc indenoisoquinolin 173 cha cc nhm th d vng no.
Nhng nghin cu ca Mark Cushman v cng s cho thy cc nhm
th vng B ti v tr nguyn t Nit (N-6) l cc nhm aminopropyl,
morpholinopropyl, imdazolopropyl cho kh nng gy c t bo rt tt, trong
c 2 hp cht ang c th nghim lm sng giai on II l Indotecan (5)
v Indimitecan (6) [6,8,15,22,42,44]. Trn c s lun n l thit k tng
hp cc indenoisoquinolin mi, khi a thm nhm hydroxyl vo v tr th 2
ca nhm propyl cn v tr th 3 l cc d vng no morpholin, piperidin,
pyrrolidin. Vi hy vng nhm hydroxyl a vo s tng kh nng tng tc
ca cc nhm th vng B ca Indenoisoquinolin vi DNA v Top1 ti v tr
phn ct ca topoisomerase I.
Cc dn xut indenoisoquinolin 173 cha cc d vng no c tng khi
cho hp cht 171 phn ng vi vi 1,5 ng lng cc amin vng no nh
morpholin, 4-Metylpiperidin, piperidin, pyrrolidin trong dung mi axeton
nhit 65 oC cng 2 ng lng cht xc tc K2CO3 thu c cc hp cht
173a , 173b, 173c, 173d vi hiu sut tng ng l 73 %, 78 %, 76%, 68 %.
129
gn vi nhn indenoisoquinolin cng hng ti H 4,75 ppm ( 1H, dd, J =
5,0; 14,5 Hz) v H 4,51 ppm (1H, dd, J = 6,5, 14,5 Hz), mt tn hiu cng
hng ca proton H-2 cng hng ti H 4,20 ppm (1H, m) cng tn hiu ca
hai proton H-3 cng hng ti H 2,51-2,49 ppm (2H, m, 2H-3). Tn hiu
ca 8 proton vng morpholin cng hng chng lp ti hai chuyn dch
khc nhau bao gm 4 proton H-2, H-4 cng hng ti H 3.79-3.68 ppm
(4H, m) v 4 proton H-1, H-3 cng hng ti H 2.67-2.60 ppm (4H, m).
Tn hiu cng hng ca 8 proton khung indenoisoquinolin cng c thy r
trn ph ti cc chuyn dch: H 8,71 ppm (1H, d, J = 8,0 Hz, H-1); H 8,31
ppm (1H, d, J = 8,0 Hz, H-4); H 7,93 ppm (1H, d, J = 7.5 Hz, H-7); H 7,72
ppm (1H, td, J = 1,0; 7,0 Hz, H-2); H 7,60 ppm (1H, d, J = 7,0 Hz, H-10); H
7,43-7,47 ppm (2H, m, H-3, H-8); H 7,37 ppm (1H, t, J = 7,5 Hz, H-9).
130
Hnh 3.4.9. Ph 1H-NMR gin rng ca hp cht 173a
13
Trn ph C-NMR ca hp cht 173a xut hin y tn hiu cng
hng ca 23 nguyn t cacbon. Trong tn hiu ca nhm cacbonyl xeton
(C-11) cng hng ti 190,6 ppm. Nhm cacbonyl amit (C-5) cng hng ti
164,38 ppm. Tn hiu ti cng hng ca cacbon ti C 66,59 ppm c quy
kt cho cacbon C-2, tn hiu ca cacbon nhm CH 2 ni vi nhn
indenoisoquinolin cng hng ti C 48.68 ppm (C-1), tn hiu cng hng
ti C 62,77 ppm c trng cho cng hng ca cacbon C-3, tn hiu ca 4
cacbon vng morpholin cng hng chng lp ti cc chuyn dch C
67.02 ppm (C-2+C-4), C 53.8 ppm (C-1 + C-3). Qua cc d kin va
phn tch cng cc d liu ph chi tit trn cho php khng nh cu trc
ca hp cht 173a.
131
Hnh 3.4.10. Ph 13C-NMR ca hp cht 173a
Tng t cu trc ca cc hp cht 173b, 173c, 173d cng c chng
minh. Nh vy lun n tng hp c 4 dn xut mi ca
indenoisoquinolin vi cc nhm th vng B l 2-hydroxy-3-
morpholinopropyl, 2-hydroxy-3-(4-metylpiperidin-1-yl)propyl, 2-hydroxy-3-
(piperidin-1-yl)propyl, 2-hydroxy-3-(pyrrolidin-1-yl)propyl. Cc cht ny
cht ny s tip tc c th hot tnh chng ung th.
132
indeno[1,2-c]isoquinolin-5,11(6H)-ion (173f) vi hiu sut tng ng l 65
%, 81 %.
133
H 4,30 ppm (1H, dd, J = 8,0; 14.5Hz), mt tn hiu cng hng ca proton
H-2 cng hng ti H 3,86-3,90 ppm (1H, m) cng tn hiu ca hai proton
H-3 cng hng ti H 3,49-3,43 ppm (2H, m, 2H-3) v mt tn hiu cng
hng singlet ti H 3,05 (1H, s, OH). Tn hiu cng hng ca 8 proton
khung indenoisoquinolin cng c xut hin y ti cc chuyn dch
H: 8,35 ppm (1H, d, J = 8,5 Hz, H-1), 7,96 ppm (1H, d, J = 8,0 Hz, H-4),
7,65 ppm (1H, d, J = 7,5 Hz, H-7), 7,42 ppm (1H, t, J = 8,0 Hz, H-2), 7,25
(1H, d, J = 7,0 Hz, H-10), 7,14-7,18 ppm (2H, m, H-3; H-8), 7,08 (1H, t, J =
13
7,5 Hz, H-9). Trn ph C-NMR ca hp cht 173e xut hin tn hiu ca
nhm cacbonyl xeton (C-11) cng hng ti C 190,08 ppm. Nhm cacbonyl
amit (C-5) cng hng chng lp vi cacbon (C=NH) ti C 164,1 ppm. Tn
hiu ti cng hng ca cacbon ti C 63,6 ppm c quy kt cho cacbon C-
3, tn hiu ca cacbon nhm CH 2 ni vi nhn indenoisoquinolin cng hng
ti C 46.89 ppm (C-1), tn hiu cng hng ti C 69,7 ppm c trng cho
cng hng ca cacbon c nhm th hydroxyl C-2.
134
Ngoi ra ph khi ca hp cht cho pic ion [M]+ m/z = 386,8 ph hp
vi cng thc phn t ca 173e l C21H17N5O3. Qua cc d kin va phn tch
cng cc d liu ph chi tit trn cho php khng nh cu trc ca hp cht
173e. Tng t cu trc ca hp cht 173f cng c chng minh.
135
proton nhm th Boc-piperazin v 5 proton mch ni. Tn hiu ca 5 proton
mch ni gia nhn indenoisoquinolin v vng piperazin bao gm hai tn hiu
cng hng ca 2 proton H a-1 v H b-1 ca nhm metylen gn vi nhn
indenoisoquinolin cng hng ti H 4,75 ppm ( 1H, dd, J = 5,0; 14,5 Hz) v
H 4.52 ppm (1H, dd, J= 7,0; 14,5 Hz), mt tn hiu cng hng ca proton
H-2 cng hng ti H 4,16- 4,22 ppm (1H, m) cng tn hiu ca hai proton
H-3 cng hng ti H 2,65 ppm (2H, d, J= 7.0 Hz). Tn hiu ca 8 proton
vng piperazin gn nhm th Boc cng xut hin y bao gm mt tn hiu
cng hng chng lp ca 4 proton H-2, H-3 cng hng ti H 3,39-3,43
ppm (4H, m), mt tn hiu cng hng ca 2 proton H-1 cng hng ti H
2,58-2,60 (2H, m) , tn hiu cng hng ca proton H-3 cng hng ti H
2,42-2,46 ppm (2H, m) cn tn hiu cng hng ca 9 proton nhm Boc cng
hng ti H 1.45 ppm (9H, s, 3CH 3). Tn hiu cng hng ca 8 proton
khung indenoisoquinolin cng c thy r trn ph ti cc chuyn dch:
H 8,70 ppm (1H, d, J = 8,5 Hz, H-1), H 8,30 ppm (1H, d, J = 8,0 Hz, H-4),
H 7,92 ppm (1H, d, J = 7,5 Hz, H-7), H 7,71 ppm (1H, td, J = 1,0; 8,0 Hz, H-
2), H 7,60 ppm (1H, d, J = 7,0 Hz, H-10), H 7,42-7,46 ppm (2H, m, H-3, H-
8), H 7,37 ppm (1H, t, J = 7,5 Hz, H-9).
136
Hnh 3.4.14. Ph 1H-NMR gin rng ca hp cht 173g
13
Trn ph C-NMR ca hp cht 173g xut hin y tn hiu cng
hng ca 23 nguyn t cacbon. Trong tn hiu ca nhm cacbonyl xeton
(C-11) cng hng ti C 190,6 ppm. Nhm cacbonyl amit (C-5) cng hng
ti C 164,39 ppm. Cc tn hiu cng hng ca cacbon trong nhm Boc bao
gm tn hiu cng hng ca cacbonyl ( COOC(CH3)3) cng hng ti C
154,66 ppm, tn hiu cng hng ca cacbon C(CH3)3 cng hng ti C
79,89 ppm cng tn hiu cng hng ca 3 cacbon nhm metyl C(CH3)3 cng
hng ti C 28,40 ppm. Tn hiu cng hng ca cacbon ti C 66,80 ppm
c quy kt cho cacbon C-2, tn hiu ca cacbon nhm CH2 ni vi nhn
indenoisoquinolin cng hng ti C 48.6 ppm (C-1), tn hiu cng hng ti
C 62,36 ppm c trng cho cng hng ca cacbon ni vi nit vng
piperazin cacbon C-3, tn hiu ca 4 cacbon vng piperazin cng hng
chng lp ti C 53.28 ppm . Qua cc d kin va phn tch cng cc d liu
ph chi tit trn cho php khng nh cu trc ca hp cht 173g.
137
Hnh 3.4.15. Ph 1H-NMR gin rng ca hp cht 173g
Tng t cu trc ca cc hp cht 173h, 173i, 173j cng c chng
minh. Nh vy lun n tng hp c 4 dn xut mi ca
indenoisoquinolin vi cc nhm th vng B cha nhm 2-hydroxy-3-
(piperazin-1-yl)propyl v dn xut. Cc cht ny s c th hot tnh gy
c t bo trn cc dng t bo ung th biu m biu b ming (KB), ung th
gan (Hep G2).
138
indeno[1,2-c]isoquinolin-5,11(6H)-ion (174b) vi hiu sut tng ng l 64
%, 65 %.
139
ppm (1H, dt, J = 1,0; 8,0 Hz, H-2), H 7,47-7,49 ppm (1H, d, m, H-10), H
7,22-7,37 ppm (1H, t, J =1,0; 8,0 Hz, H-3).H 7,42-7,46 ppm (3H, m, H-3,
H-8, H-9).
140
5) cng hng ti C 164,1 ppm. Tn hiu ca cacbon ni vi nhm metoxi
(C-OCH3) cng hng ti C 156,31 ppm. Tn hiu cng hng ca cacbon ti
C 37,3 ppm c quy kt cho cacbon C-3, tn hiu ca cacbon nhm CH2
ni vi nhn indenoisoquinolin cng hng ti C 48.6 ppm (C-1), tn hiu
cng hng ti C 69,7 ppm c trng cho cng hng ca cacbon c nhm
th hydroxyl C-2, tn hiu ca cacbon nhm metoxi (OCH3) cng hng ti
C 55.7 ppm. Ngoi ra ph khi ca hp cht cho pic ion [M +H]+ m/z = 483,9
ph hp vi cng thc phn t ca 174b l C27H24N 3O 4S. Qua cc d kin
va phn tch cng cc d liu ph chi tit trn cho php khng nh cu
trc ca hp cht 174b.
141
3.5. Tng hp cc indenoisoquinolin i t 6-(2,3-ihydroxypropyl)-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion.
Nhng nghin cu tng hp, hot tnh gy c trn cc dng t bo ung
th v hot tnh c ch Top1 ca cc dn cht indenoisoquinolin c cha
mch nhnh l cc ancol, iol v aminoancol c Mark Cushman v cng
s nghin cu vi kt qu hp cht 6-(2,3-ihydroxypropyl)-3-nitro-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion (87b) c hot tnh cao hn so cc
thuc camptothecin, Topotecan v Irinotecan [4]. Trn c s lun n
tin hnh tng hp thnh cng 6-(2,3-ihydroxypropyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (175) v tng hp cc dn xut mi ca
indenoisoquinolin trn c s phn ng este ha gia 6-(2,3-ihydroxypropyl)-
5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion vi MsCl, TsCl, anhirit
isobutyric, anhirit axetic nh s :
Hp cht 6-(2,3-ihydroxypropyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (175) c tng hp khi cho hp cht 171 phn ng vi H2O
trong dung mi axetonitrin (axetonitrin/H2O = 40/1) nhit 60 oC trong
18h thu c sn phm l mt cht rn c mu vng sng, c nhit nng
142
chy 209-211 oC. Cu trc ca sn phm c xc nh da trn cc d kin
ph IR, 1H-NMR, 13C-NMR.
143
d, J = 8,0 Hz, H-4), H 7,80 ppm (1H, d, J = 7,5 Hz, H-7), H 7,67 ppm (1H, t,
J = 7,5 Hz, H-2), H 7,54 ppm (1H, d, J = 7,0 Hz, H-10), H 7,38-7,42 ppm
(2H, m, H-3; H-8), H 7,32 ppm (1H, t, J = 7,0 Hz, H-9).
144
Hnh 3.5.3. Ph 13C-NMR ca hp cht 175
145
proton trn khung cu trc ca phn t. Vng trng thp l tn hiu cng
hng ca 8 proton thm ca nhn indenoisoquinolin. Tn hiu doublet cng
hng ti H 8,60 ppm vi hng s tng tc J = 8,0 Hz l c trng ca
proton H-1. Tn hiu doublet vi hng s tng tc 8,0 Hz ti H 8,22 ppm l
c trng cng hng ca proton H-4. Proton v tr H-7 cng hng doublet
ti H 7,96 ppm vi hng s tng tc J = 7,5 Hz, Proton v tr H-2 cng
hng ti H 7,83 ppm vi hng s tng tc J = 8,0 Hz. Ba proton ca nhn
indenoisoquinolin l H-3, H-8 v H-10 c tn hiu cng hng chng lp
trong khong H 7,52-7,56 ppm, tn hiu ca proton H-9 cn li cng hng
ti H 7,48 ppm (1H, t, J = 7,5 Hz). Cc tn hiu cng hng ca proton mch
nhnh cng xut hin y vng trng cao hn. Tn hiu cng hng
ca mt proton vi hng s tng tc ln ti H 4,63 ppm (1H, dd, J = 4,5;
14,5 Hz) c quy kt cho proton H a-1 ca nhm metylen mch nhnh gn
vi nhn indenoisoquinolin, tn hiu cng hng ca proton Hb-1 cn li
cng hng ti H 4,50 ppm ( 1H, dd, J = 8,5; 14,5 Hz), hai tn hiu doublet-
doublet cng hng ti H 4,41 ppm (1H, dd, J = 4,0; 10,5 Hz) v H 4,35
ppm (1H, dd, J = 5,5; 10,5 Hz) vi hng s tng tc ln c quy kt cho
proton Ha-3 v H b-3, tn hiu cng hng c trng ca proton H-2 cng
hng ti H 4,26-4,29 (1H, m).Tn hiu cng hng ca nhm hydroxyl
cng hng ti H 5,73 (1H, d, J = 5,5 Hz, OH). Tn hiu cng hng ca
nhm metyl cng hng ti H 3,24 (3H, s, CH 3). Ngoi ra cu trc ca phn
t cn c khng nh thm bi cc d kin trn ph 13C-NMR. Tn hiu ca
nhm cacbonyl xeton (C-11) cng hng ti C 190,1 ppm. Nhm cacbonyl
amit (C-5) cng hng ti C 162,7 ppm. Nhm metyl ca mch nhnh cng
hng ti C 30,6 ppm (CH3), Tn hiu cng hng ca cacbon ti C 66,1
ppm c gn cho cacbon ni vi nhm hydroxyl C-2, tn hiu ca cacbon
nhm CH2 ni vi nhn indenoisoquinolin cng hng ti C 46,7 ppm (C-1)
cng tn hiu cng hng ti C 71,8 ppm c quy kt cho cacbon C-3.
146
Qua cc d kin va phn tch cng cc d liu ph chi tit trn cho php
khng nh cu trc ca hp cht 176a. Tng t cu trc 176b cng c
chng minh.
147
3.5.2. Tng hp cc hp cht indenoisoquinolin 177
Cc hp cht indenoisoquinolin 177 c tng hp thng qua phn ng
gia hp cht 175 vi anhirit isobutyric, anhirit axetic, thu c cc hp
cht 177a , 177b vi hiu sut tng ng l 65 %, 62 %.
148
Hnh 3.5.5. Ph 1H-NMR ca hp cht 177a
Trn ph 13C-NMR ca hp cht 177a xut hin y tn hiu cng
hng ca cc nguyn t cacbon cu trc phn t. Trong tn hiu ca
nhm cacbonyl xeton (C-11) cng hng ti C 190,53 ppm. Nhm cacbonyl
amit (C-5) cng hng ti C 164,59 ppm. Nhm cacbonyl mch nhnh
(CH3CHCOO) cng hng ti C 177,14 ppm. Cc tn hiu cng hng ca
cacbon nhm th cn bao gm tn hiu cng hng ca 2 cacbon nhm metyl
(2CH3) cng hng ti C 19,02 ppm, tn hiu cng hng ca cacbon CH-
(CH3)2 cng hng ti C 34,05 ppm cng cc tn hiu cng hng ca cacbon
ti C 66,45 ppm c quy kt cho cacbon C-2 tn hiu ca cacbon nhm
CH2 ni vi nhn indenoisoquinolin cng hng ti C 47.95 ppm (C-1), tn
hiu cng hng ti C 69,21 ppm c trng cho cng hng ca cacbon C-
3. Qua cc d kin va phn tch cng cc d liu ph chi tit trn cho
php khng nh cu trc ca hp cht 177a. Tng t cu trc 176b cng
c chng minh.
149
Hnh 3.5.6. Ph 13C-NMR ca hp cht 177a
150
3.6. Hot tnh gy c t bo ca cc hp cht c tng hp
Trong cc hp cht indenoisoquinolin c tng hp, chng ti tin
hnh th hot tnh gy c t bo ca 36 hp cht trn t bo ung th biu m
KB (Human epidermic carcinoma) v ung th gan Hep-G2 (Hepatocellular
carcinoma) theo phng php MTT ca Mosmann [73] ti phng Ha sinh
ng dng- Vin Ha hc - Vin Hn lm Khoa hc v Cng ngh Vit Nam.
Kt qu c trnh by ti bng 3.6.1 v 3.6.2.
151
indenoisoquinolin 169 cn li u khng th hin hoc th hin rt yu hot
tnh gy c t bo vi dng ung th kho st.
Cc hp cht indenoisoquinolin 170 u th hin hot tnh hot tnh gy
c t bo vi dng ung th kho st trong hp cht axt (S)-2-(5,11-
ioxo-5H-indeno[1,2-c]isoquinolin-6(11H)-yl)-3-phenyl propanoic (170c) th
hin hot tnh kh mnh vi vi dng t bo ung th Kb (IC50 = 4,55 M) v
th hin hot tnh trung bnh vi dng t bo ung th Hep-G2 (IC50 = 12,65
M).
152
173d, 173e, 173h, 173i, 176b th hin hot tnh gy c t ung th mnh bo
mnh vi gi tr IC50 < 5 M.
Trong cc cht th hin hot tnh gy c t bo ung th mnh, c 3
hp cht th hin hot tnh gy c t bo tng ng vi cht i chng
Ellipticine: 6-(2-hydroxy-3-(4-metylpiperidinyl)propyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion (173b, IC50 = 1,79 M (KB), 2,23 M (Hep-
G2)), 6-(2-hydroxy-3-(piperidinyl)propyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (173c, IC50 = 1,67 M (KB), 1,15 M (Hep-G2)), 6-(2-
hydroxy-3-(4-metylpiperazinyl)propyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (173h, IC50 = 1,51 M (KB), 1,19 M (Hep-G2).
c bit c 2 hp cht tng hp c th hin hot tnh gy c t bo
ung th kho st mnh hn c cht i chng Ellipticine: 6-(2-hydroxy-3-
morpholinopropyl)-5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion (173a, IC50 =
0,82 M (KB), 0,47 M (Hep-G2)) v 6-(2-hydroxy-3'-(piperazin-1-
yl)propyl)-5H-indeno[1,2-c]isoquinolin-5,11(6H)-ion (173i, IC50 = 0,82 M
(KB), 0,69 M (Hep-G2)).
Kt qu trn cng cho thy cc indenoisoquinolin c nhm th propyl
vng B v thit k a thm nhm hydroxyl vo v tr th 2 ca nhm
propyl cn v tr th 3 l cc d vng morpholin, piperidin, pyrrolidin,
piperazin cho hot tnh gy c t bo mnh, u cho hot tnh cao hn hp
cht gc 6-(3-bromo-2-hydroxypropyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion (171). Trong cc indenoisoquinolin c hot tnh mnh vi
dng ung th kho st th kh nng c ch ca cc indenoisoquinolin c
tng hp vi dng t bo ung th gan (Hep-G2) thng mnh hn t bo ung
th biu m (KB).
153
O O O
CH3
OH OH O OH
N N N N N N
O 173c
O 173a O 173b
IC 50 = 0.82 M (KB),0.47 M (Hep-G2) IC50 = 1.79 M (KB), 2.23 M (Hep-G2) IC 50 = 1.67M (KB), 1.15 M (Hep-G2)
O O O
OH OH N OH NH
N N N N N N
O 173h O 173i
O 173d
IC50 = 2.35 M (KB), 3.44 M (Hep-G2) IC50 = 1.51 M (KB),1.19 M (Hep-G2) IC 50 = 0.82 M (KB), 0.69 M (Hep-G2)
O O O
OH OH O
H
N N O S CH3
N Br
O
O 178b
171 170c O COOH
O
IC50 = 5.2 M (KB),3.3 M (Hep-G2) IC 50 = 4.55M (KB),12.65M (Hep-G2) (IC50 = 4.3M (KB),7.19 M (Hep-G2)
O O O
OH Br
H H N O Boc
N N N O N
CN N Br H
O 169l
O 173e NH O 172
IC 50 = 2.50 M (KB),2.99 M (Hep-G2) IC50 = 3.4M (KB), 2.05M (Hep-G2) IC 50 = 1.82M (KB),1.41M (Hep-G2)
154
KT LUN
155
NHNG IM MI CA LUN N
156
CC CNG TRNH CNG B LIN QUAN N LUN N
1. Lc Quang Tn, ng Th Tuyt Anh, Nguyn Vn Tuyn, Nghin
cu tng hp mt s dn xut ca Indenoisoquinolin c hot tnh chng ung
th , Tp ch Ha hc, Tr 534-537, T51(2AB), 2013.
2. Lc Quang Tn, Nguyn Vn Tuyn, Nghin cu tng hp mt s
dn xut mi ca indenoisoquinolin c nhn thm mch nhnh v hot tnh
gy c t bo, Tp ch Ha hc, Tr 82-85, T51(6ABC), 2013.
3. Lc Quang Tn, Nguyn Vn Tuyn, Nguyn Bch Thun, Hong
Th Phng, Tng hp 6-(2-Metoxyetyl)-5H-indeno[1,2-c]isoquinolin-
5,11(6H)-ion, Tp ch khoa hc Trng HSP H Ni 2, Tr 149-154, S
26, 2013.
4. Lc Quang Tn, Trng Th Kim Loan, ng Th Tuyt Anh,
Nguyn Vn Tuyn, Tng hp 6-(2,3-ibromopropyl)-5H-indeno[1,2-
c]isoquinolin-5,11(6H)-ion, K yu Hi tho khoa hc cn b tr cc
trng i hc s phm ton quc ln th IV, Tr 584-588, 2014.
5. Luc Quang Tan, ang Thi Tuyet Anh, Pham The Chinh, Pham Thi
Tham, Nguyen Van Tuyen, Synthesis of new indenoisoquinoline analogs,
Proceedings of the first VAST-BAS workshop on sience and technology, p.
429-432, 2014.
6. Lc Quang Tn, ng Th Tuyt Anh, Phm Th Chnh, Phm Th
Thm, Nguyn Vn Tuyn, Nghin cu tng hp mt s dn xut mi
Indenoisoquinolin t indeno[1,2-c]isochromen-5,11-ion v L--amino axt,
Tp ch Ha hc, Tr 204-207, T51(2AB), 2014.
7. Lc Quang Tn, Phm Th Thm, ng Th Tuyt Anh, Nguyn H
Thanh, Nguyn Vn Tuyn, Nghin cu tng hp 6-(10-aminodecyl)-5H-
indeno[1,2-c]isoquinolin-5,11(6H)-ion, Tp ch Ha hc v ng dng,
(c chp nhn ng s 1 nm 2016).
8. Tham Pham Thi, Lena Decuyper, Tan Luc Quang, Chinh Pham The,
Tuyet Anh Dang Thi, Ha Thanh Nguyen, Thuy Giang Le Nhat, Tra Nguyen
Thanh, Phuong Hoang Thi, Matthias D'hooghe, Tuyen Van
NguyenSynthesis and cytotoxic evaluation of novel indenoisoquinoline-
propan-2-ol hybrids, Tetrahedron Letters.(In Press, Accepted Manuscript.
Available online 9 December 2015).
157
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1. Andrew Morell, Michael Placzek, SethParmley, SmithaAntony, Thomas S.
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Chemistry, 2003, 46, 3275 3282 .
3. Martin Conda-Sheridan, Eun-Jung Park, Daniel E. Beck, P. V. Narimha
Reddy, Trung X. Nguyen, Bingjie Hu, Lian Chen, Jerry J. White, Richard B.
van Breemen, John M. Pezzuto, v Mark Cushman, Design, Synthesis, and
Biological Evaluation of Indenoisoquinoline Rexinoids with
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4. Katherine E. Peterson, Maris A. Cinelli, Andrew E. Morrell, Akhil Mehta,
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Cushman, Alcohol-, Diol-, and Carbohydrate- Substituted
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Activity, Journal of Medicinal Chemistry, 2011, 54, 4937 4953.
5. Gang Ahn, Nadge Schifano-Faux, Jean-Francois Goossens, Brigitte
Baldeyrou, Axel Couture, Pierre Grandclaudon, Amlie Lansiaux, Adina
Ryckebusch, Synthesis, cytotoxicity and topoisomerase inhibition properties
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Bioorganic & Medicinal Chemistry Letters, 2011, 21, 2259 2263.
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158
indenoisoquinolines as topoisomerase I inhibitors, Bioorganic & Medicinal
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isoquinolones to indeno[1,2-c]isoquinolines by thionyl chloride,
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8. Maris A. Cinelli, P. V. Narasimha Reddy, Peng-Cheng Lv, Jian-Hua Liang,
Lian Chen, Keli Agama, Yves Pommier, Richard B. van Breemen, and Mark
Cushman, Identification, Synthesis, and Biological Evaluation of
Metabolites of the Experimental Cancer Treatment Drugs Indotecan
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Hydroxylated Indenoisoquinoline Analogues as Topoisomerase I Poisons,
Journal of Medicinal Chemistry, 2012, 55, 1084410862.
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Mark Cushman, Synthesis of benz[d]indeno[1,2-b]pyran-5,11-diones:
Versatile intermediates for the design and synthesis of topoisomerase I
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10. Mark Cushman, Muthusamy Jayaraman, Jeffrey A. Vroman, Anna K.
Fukunaga, Brian M. Fox, Glenda Kohlhagen, Dirk Strumberg, and Yves
Pommier, Synthesis of New Indeno[1,2-c]isoquinolines: Cytotoxic Non-
Camptothecin Topoisomerase I Inhibitors, Journal of Medicinal Chemistry,
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11. Muthusamy Jayaraman, Brian M. Fox, Melinda Hollingshead, Glenda
Kohlhagen, Yves Pommier, v Mark Cushman, Synthesis of New
Dihydroindeno[1-2]isoquinoline and Indenoisoquinolineium Chloride
Topoisomerase I Inhibitors Having High in Vivo Anticancer Activity in the
Hollow Fiber Animal Model, Journal of Medicinal Chemistry, 2002, 45,
242- 249.
12. Muthukaman Nagarajan, Andrew Morrell, Brian C. Fort, Marintha Rae
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159
Cushman, Synthesis and Anticancer Activity of Simplified
Indenoisoquinoline Topoisomerase I Inhibitors Lacking Substituents on the
Aromatic Rings, Journal of Medicinal Chemistry, 2004, 47, 5651-5661.
13. Dirk strumberg, Yves Pommier, Kenneth Paull, Muthusamy Jayaraman,
Pamela Nagafuji, and Mark Cushman, Synthesis of Cytotoxic
Indenoisoquinoline Topoisomerase I Poisons, Journal of Medicinal
Chemistry, 1999, 42, 446-457.
14. Daulat Bikram Khadka, Won-Jea Cho, 3-Arylisoquinolines as novel
topoisomerase I inhibitors, Bioorganic & Medicinal Chemistry, 2011, 19,
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15. Daniel E. Beck, Keli Agama, Christophe Marchand, Adel Chergui, Yves
Pommier, and Mark Cushman, Synthesis and Biological Evaluation of New
Carbohydrate-Substituted Indenoisoquinoline Topoisomerase I Inhibitors and
Improved Syntheses of the Experimental Anticancer Agents Indotecan
(LMP400) and Indimitecan (LMP776), Journal of Medicinal Chemistry,
2014, 57, 14951512.
16. Hue Thi My Van, Quynh Manh Le, Kwang Youl Lee, Eung-Seok Lee,
Youngjoo Kwon, Tae Sung Kim, Thanh Nguyen Le, Suh-Hee Lee and Won-
Jea Cho, Convenient synthesis of indeno[1,2-c]isoquinolines as constrained
forms of 3-arylisoquinolines and docking study of a topoisomerase I inhibitor
into DNA-topoisomerase I complex, Bioorganic & Medicinal Chemistry
Letters, 2007, 17, 5763-5767.
17. Won-Jea Cho, Quynh Manh Le, Hue Thi My Van, Kwang Youl Lee, Bok
Yun Kang, Eung-Seok Lee, Sang Kook Lee and Youngjoo Kwon, Design,
docking, and synthesis of novel indeno[1,2-c]isoquinolines for the
development of antitumor agents as topoisomerase I inhibitors, Bioorganic
& Medicinal Chemistry Letters, 2007, 17, 3531-3534.
18. Prakash G.jagtap, Erkan Baloglu, Garry J. Southan,Jon G. Mabley,
Hongshan Li, Jing Zhou, John van Duzer, Andrew L. Salzman, va Csaba
Szab, Discovery of Potent Poly(ADP-ribose) Polymerase-1 Inhibitors from
160
the Modification of Indeno[1,2-c]isoquinolinone, Journal of Medicinal
Chemistry, 2005, 48, 5100-5103.
19. Daulat Bikram Khadka, Quynh Manh Le, Su Hui Yang, Hue Thi My Van,
Thanh Nguyen Le, Suk Hee Cho, Youngjoo Kwon, Kyung- Tae Lee, Eung-
seok Lee, Won- Jea Cho,Design, synthesis and docking study of 5-amino
substituted indeno[1,2-c]isoquinolines as novel topoisomerase I inhibitors,
Bioorganic & Medicinal Chemistry, 2011, 19, 19241929.
20.Alexandra Ioanoviciu, Smitha Antony, Yves Pommier, Bart L. Staker,
Lance Stewart and Mark Cushman, Synthesis and Mechanism of Action
Studies of a Series of Norindenoisoquinoline Topoisomerase I Poisons Reveal
an Inhibitor with a Flipped Orientation in the Ternary DNA-Enzyme-Inhibitor
Complex As Determined by X-ray Crystallographic Analysis, Journal of
Medicinal Chemistry, 2005, 48, 4803-4814.
21. Meslanie Dubois, Stphane Lebrun, Axel Couture, Eric Deniau, Pierre
Grandclaudon, Alternative synthetic approaches to biologically active
indeno[1,2-c]isoquinoline-5,11-diones, 15th international electronic
conterence on synthetic organic chemistry, 2011.
22. Trung Xuan Nguyen, Monica Abdelmalak, Christophe Marchand, Keli
Agama, Yves Pommier, and Mark Cushman, Synthesis and Biological
Evaluation of Nitrated 7, 8, 9, and 10-Hydroxyindenoisoquinolines as
Potential Dual Topoisomerase I (Top1)Tyrosyl-DNA Phosphodiesterase I
(TDP1) Inhibitors, Journal of Medicinal Chemistry, 2015, 58, 31883208.
23. Stphane Lebrun , Axel Couture , Eric Deniau , Pierre Grandclaudon,
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combination to the synthesis of indeno[1,2-c]isoquinolin-5,11-diones,
Tetrahedron Letters, 2011, 52, 14811484.
24. Muthukaman Nagarajan, Andrew Morrell, Smitha Antony, Glenda
Kohlhagen, Keli Agama, Yves Pommier, Patricia A. Ragazzon, Nichola C.
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Synthesis and Biological Evaluation of Bisindenoisoquinolines as
161
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25. Muthukaman Nagarajan, Andrew Morrell, Alexandra Ioanoviciu, Smitha
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26. Lian Chen, Martin Conda-Sheridan, P. V. Narasimha Reddy, Andrew
Morrell, Eun-Jung Park, Tamara P. Kondratyuk, John M. Pezzuto, Richard B.
van Breemen, and Mark Cushman, Identification, Synthesis, and Biological
Evaluation of the Metabolites of 3-Amino-6-(3-aminopropyl)-5H-indeno[1,2-
c]isoquinoline-5,11-(6H)dione (AM636), a Promising Rexinoid Lead
Compound for the Development of Cancer Chemotherapeutic and
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27. Andrew Morrell, Michael S. Placzek, Jamin D. Steffen, Smitha Antony,
Keli Agama, Yves Pommier, and Mark Cushman, Investigation of the
Lactam Side Chain Length Necessary for Optimal Indenoisoquinoline
Topoisomerase I Inhibition and Cytotoxicity in Human Cancer Cell Cultures,
Journal of Medicinal Chemistry, 2007, 50, 2040-2048.
28. Martin Conda Sheridan, P. V. Narasimha Reddy, Andrew Morrell,
Brooklyn T. Cobb, Christophe Marchand, Keli Agama, Adel Chergui, Amlie
Renaud, Andrew G. Stephen, Lakshman K. Bindu, Yves Pommier v Mark
Cushman, Synthesis and Biological Evaluation of Indenoisoquinolines That
Inhibit Both Tyrosyl-DNA Phosphodiesterase I (Tdp1) and Topoisomerase I
(Top1), Journal of Medicinal Chemistry, 2013, 56, 182200.
29. Trung Xuan Nguyen, Andrew Morrell, Martin Conda-Sheridan,
Christophe Marchand, Keli Agama, Alun Bermingam, Andrew G. Stephen,
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162
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32. Gang Ahn, Amlie Lansiaux, Jean-Francois Goossens, Christian Bailly,
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34. Evgeny Kiselev, Sean DeGuire, Andrew Morrell, Keli Agama, Thomas S.
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