Anti-cancer compounds / Antineoplastic Agents, chapter 38

Cancer Therapy
•Surgery
•Radiation
•Immunologican Therapy (interferons - Incr. prod. T-cells and B cells)
•Chemotherapy
•Alkylation Agents
•Antimetabolites / Nucleoside Analogs
•Antibiotics
•Antimitotic Agents
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
Antimetabolites (Nucleoside Analogs, Folic acid analogs)

Antimetabolites: Prevents synthesis of normal cellular metabolites

Often close structural similarities metabolite and antimetabolite

earlier ex. PABA / sulfonamides O

OH NH
N CO2H
N N
H
H2N N N
Antibact. sulfonamide CO2H
O R O Folic acid
H2N S NH
OH OH
O
N
N N
O H From diet, humans
H2N H2N N N
OH H
PABA Dehydropteridinsyre

O O

OH NH OH NH
H
CO2H Folate- N CO2H
N reduktase N
N N N
H H
H2N N N H2N N N
H H CO2H
CO2H
Tetrahydrofolic acide Trimetoprim Dihydrofolic acid
NH2
OCH3
N
Essential processes
bacteria and animals H2N N OCH3
ex. Thymin synthesis OCH3
(Metab. CH3OH)
Nucleoside analogs as antimetabolites

Possible mecanisms:
• Incorporation DNA or RNA; misreading
• Inhibition of DNA polymerase
• Inhibition of Kinases
• Inhib. of enzymes involved in pyrimidine / purine biosynthesis

O NH2 O
NH2
DNA HN N
N N HN N

O N O N N H2N N N
N
O O
Thymin Cytosin Adenine Guanine P
O
O Base
O
O
R=H in DNA
R=OH in RNA
RNA HN O R
Cytosin Adenine Guanine
O N

Uracil
 O
5-Fluoruracil (5-FU) O
HN
F
Fluorouracil®, Flurablastin®, F
HN in vivo
O O N Inhibitor
O N HO P O Thymidylate synthetase
H O
OH

HO

O
O HN
O O HO2C
HN O O N
P +
H2N O OH O N CO2H HO P O UMP
OH H2N CO2H O
H OH
Carbamoyl phosphate Asp Orotic acid
HO

HN More common route in cancer cells

5-FU more easily activated in cancer cells (?)
O N
H
Uracil
 Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase
Tetrahydrofolate NH2
HN
O N
NH2
HN O
N NH
O N
O HN
H
N NH
HN N5N10.Methylene Tetrahydrofolate O O N H NH
N HO P O B R
O O N R O S
OH
HO P O O H Thymidylate
OH B Synthetase
HS HO
Thymidylate
HO
Synthetase

UMP NH2
HN
O N

N NH
O O
O H
NH
HN HN
HN R
O O N O O N H
H O O N H
HO P O HO P O B H
O O S HO P O B
O S
OH OH
OH
Thymidylate
Thymidylate
Synthetase
HO HO NH2 Synthetase
HO
HN
O N
TMP
N NH

NH
R
 NH2
NH2 HN
HN O N
O N
O O
F N NH
N NH
HN HN
N F
O O N R O O N H NH
HO P O HO P O B R
O H O S
OH B OH
HS
Thymidylate
Kapecitabin
HO
Thymidylate
Synthetase
HO
Synthetase Xelodar®,
O
5-FU metabolite
Enzyme inhibition
HN O
F
Additional mechanisms: Incorp. DNA / RNA N

O N
O Pro-drog 5-FU

HO
5-FU metabolism
Tegafur
O Dihydropyrimidine O UFT®
dehydrogenase F
F HN
HN H O
Inactive metabolite O
O N O N F
H HN
H + HN
O O N O N
O H
HN Additive in some 5-FU preparates (Not in N)
Inhib.
O N Dihydropyrimidine
H 5-FU prodrug dehydrogenase
 Cytarabine (ARA-C)
Cytarabin®, Cytosar®,
NH2 NH2 NH2
NH2
N N N
N

metabolic activation O N O N O N
O N
P P P O P O O P O O
HO O O
OH OH

HO HO OH HO
HO

ARA-C Metabolic ARA-C

inactivation
(fast) Inhib. DNA polymerase

O
Incorporation DNA/RNA; misreading

HN

O N
HO O
OH

HO

NH2
Gemcitasbin N
Gemzar®, Metabolic activation (triphophate)
O N
HO O
Incorp. DNA / RNA
F

HO F
6-Mercaptopurine (6-MP)
Puri-Nethol®

S-Analog hypoxanthine
SH S S S Me
Metabolic
N N HN N activation HN N N N

N N N N N N N N
H H
P O P O
O O
6-MPMP
Inhib. several steps
HO OH in purine biosynth HO OH
also antimetabolite

HN N

N N
P P P O
O

HO OH
Incorp . DNA / RNA instead og guanine

HN N NO2
N
H2N N N
H N S
Me 6-MP pro-drug
N N used before
6-thioguanine (not drug in N)
≈ 6-MP activity N N
H
 O O O
N HN N N
HN HN
P O H P O NH2 N N N
O O N O N H2N N
P O H
O P O P O P O O P O O
HO OH HO OH
HO OH OH OH
O NH2 HO HO
O OH

H2N CO2H H2N CO2H NH2

glutamine glutamate N N Inhib by 6-MP metabolite

N N
P O O

HO OH

Fludarabine Cladribin
Fludara® Leustatin®
NH2

N N NH2

N N
F N N
Not really antimetabolite
Cl N N
Not good substrate for HO O
Inhib. repair enzymes
adenosine deaminase OH HO O
Antimetabolite
HO
HO
Folic Acid analogs as antimetabolites
PABA

Microorganisms

O CO2H
R R
DHFR O DHFR O
O N CO2H H
H N N
N HN N HN N
HN N H H
H
H2N N N H2N N N
H2N N N H H
Folic acid
Dihydrofolate Tetrahydrofolate

Metotreksat O N
Metoject® N
O CO2H HN

NH2 N CO2H H2N N N

H H
N
N N

H2N N N Thymine synth

O CO2H
Trimetoprim
Raltitrexed O S N CO2H NH2
N H
Tomudex® HN N N
OCH3

N N H2N N OCH3
OCH3
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics
•Antimitotic Agents
•Micellaneous Antineoplastic Agents
•Hormonal Therapy

Metabolites from microorg., too toxic as antibiotics - anticancer comp.

•Bleomycins
•Actinomycins
•Mitomycins
•Antracyclins
•Coformycins
Bleomycins

Isolated from Streptomyces verticillius

Naturally occuring as Cu-chelates 1) Binds Fe(II) inside cells

H2N O
H2N O

O NH2
O NH
NH OH
H2N NH N O2
OH H2N NH
N Fe
N N O N
HO N N
N
H2N O OH N
H2N
O OH
O NH O O
NH2
HO
OH O 2) Bleomycin complexed Fe(II) reduce O2
O
OH
NH
Bleomycine A: R = S(CH3)3
3) .OH radicals produced
HN O
H
4) Cleavage of DNA
N NH2
Bleomycibe B: -CH2
N NH2
S

N DNA binding
O
S
Interact heterocycl. bases
HN
Electrostat. interact. with phosphates Bleomycin
R
Bleomycin Baxter®
Actinomycins
Isolated from Streptomyces sp.

Dactinomycin (Actinomycin D)
Cosmegen®

O
O
N
N
N
N O N
O N O
O

NH O O Planar, aromatic rings

NH O O
O
Intercalate between G-C base pairs
O (π−π stacking interact)
HN O O NH
N NH2

O O - Affects DNA topoisomerase II (Unwinding)

- May also promote DNA cleavage (nucleases)

 Quinolones
Inhib DNA-synthesis; DNA-gyrase (prokaryoter) uwounding DNA before replic..
DNA-topoisomerase (humans), anticancer compds. ex. doxorubicin
Unique mecanism, no cross resistance
Broad spectrum: G+ and G- ; also mycobactria, clamydia

Parent comp. Moderne quinolones

Nalidixic acid
must be oxo
O
CO2H F increase activity
R O
F CO2H
N N

R N
Urinary tract infect. earlier R R Essentialt
effect on Gram-negative bacteria (ex. E. coli)
Preferably H Chelater with
Ca2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+
Must have aromatic ring
condenced with the pyridine
Intramolek. N
H-bond
O
H
O O
O O
O
Met2+
N
O O

pKa ca 5.5 - 6.5 O

(Benzoic acid pKa 4.2) N
 Antibacterial Tetracyclines
Antracyclines OH
OH O HO O O
Isolated Streptomyces sp, several semisynth analogs NHR2

O OH O OH
R2
Doxorubicin R6
H H
R5 N
OH Doxorubicin® Adriamycin® Caelyx®
R1 = OMe, R2 = OH, R3 = H; R4 = OH
R1 O OH
O
R3
CH3 Daunorubicin
R4
NH2 Cerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH

Epirubicin
Idarubicin
Farmorubicin®
Zavedos® R1 = H, R2 = H, R3 = H; R4 = OH
R1 = OMe, R2 = OH, R3 = OH; R4 = H

Valrubicin
Mitoxantrone
O OH O
OCOC4H9 Novantrone®
OH H
N
OH O HN OH
OCH3O OH
O

CH3
HO OH O HN OH
N
HN H
COCF3
Mechanism ≈ Actinomycins (Intercalation)

Also interact aminosugar - phosphate

Antraquinone - red/ox react:

prod. reactive oxygen radicals

DNA-Daunomycin Complex
Mitomycins
Isolated Streptomyces sp,

Mitomycin C
Mutamycin®
In vivo:
H B
O OCONH2 OCONH2 OH OCONH2 O OCONH2
H2N H2N H2N H H2N
OCH3 red OCH3 B

N NH N NH H3C N NH H3C N NH
H3C H3C H
O OH OH OH

quinone Hydroquinone

O H
NH2
OH Nu OH O Nu O OCONH2 Nu
H2N H2N H2N
Nu DNA Nu DNA Nu DNA
H3C N H3C N H3C N
OH NH2 OH NH2 OH NH2

Active drug

OH Nu
H2N
Nu DNA
H3C N
OH NH2
Conformycins
Isolated Streptomyces sp,
Also metab. of anticancer / antiviral
adeninederiv.
NH2 H2N OH O
N HN N HN N
N Adenosine
N N deaminase N N N N
HO HO HO
O O O

HO OH HO OH HO OH

Adenine Inosine

sp3

OH
N
HN
N
HO
O

HO R

R=OH: Coformycin
R=H: DEoxycoformycin (Pentostatin)

Ex. transition state analogs

•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
 Mitosis
Prophase Metaphase Anaphase Telophase

Antimitotic agents bind to microtubuli

Supression of microtubuli dynamics

Metaphase arrest
 HO
N
Vinca alkaloids N

N
N N
N H H OCOMe
H H OCOMe
MeO2C CO2Me
MeO2C CO2Me N
N MeO OH
MeO OH CH3
R
Vinorelbine, Navelbine®
R=-Me: Vinblastin, Velbe®
R=-CHO: Vinkristin, Vincristine®
Vinca alkaloids (Indols)
from Vinca rosea
(Catharantus roseus) Binds to microtubuli- Supression of microtubuli dynamics-
MadagaskarPerivinkle Metaphase arrest

Depolymerization of microtubuli high conc.

Taxanes

First isolated from bark of Western / Pacific yew (Taxus brevifolia)

NIH screening of plant extracts 1960s

O
R1
NH R2
O
O
O
OH
HO O

HO H
O O O
O
O

R1 = -Ph, R2 = -COMe: Palitaxel, Taxol®

R1 = -OBut, R2 = -H: Dodetaxel, Taxotere® Semisynthetic

Mecanism ≈ Vinca alkaloids, different binding sites

Palitaxel
Availability

Dried inner bark of Western / Pacific yew (Taxus brevifolia): 0.01 - 0.04%
1 kg Taxol - 900 kg bark (2000 - 3000 trees)

-Other Taxus sp: Also palitaxel in needles (renewable source)

-Semisynth from deacetylbaccatin III (0.1% in needles Taxus baccata)

O
R1
OH
NH R2
O O
OH O
O
HO OH
HO O
HO H
O O O HO H
O
O O O
O O
O

Deacetylbaccatine III

(-Total syntheses)
Colchicine

From Meadow-saffron, Colchicum autumnale (Tidløs) seeds

Binds to microtubuli - metaphase arrest, too toxic too be used in cancer treatment
Used to treat gout (podagra)
O
H3CO
NH
H3CO
CH3O
O
OCH3
 Comming next? - Epothilones

Isolated from Myxobacteria (Epothilone A - F + synth. analogs)

S S S S
N N N N

O O O OH O OH
OH OH
O O
O O O O

O OH O OH O
OH OH

Epothilone A Epothilone B Epothilone C Epothilone D

OH OH
S S
N N

O OH O OH
O O
O O

OH OH O

Epothilone E Epothilone F
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents
•Hormonal Therapy
O
•Hydroxyurea OH
Hydroxykarbamid®
H N2N
•Podophyllotoxines H

•Camptothecins Inhib. ribonucleotide diphosphate reductase

•Compounds for Arrest cells in G1-S interphase
photodynamic therapy (combi with radiation)
•Tyrosine-Kinase Inhibitors
Podophyllotoxines
From Podophyllum peltarum
May apple

OH
Antiviral, veneric warts
O
O Toxic - lead for anticancer drugs
O
O

MeO OMe
OMe

Podophyllotoxin

OO
HO
HO Etoposide
O Eposin® Etopofos®
O Vepesid®
O
O
O
Affects DNA topoisomerase II (not intercalating)
MeO OMe
OH DNA strand breakage
Etoposide
Camptothecins

First isolated Camptotheca acuminata (Chinese tree)

NIH screening
Later found in several plants N
O

N
O

OH O

Camptothecin,
toxic, Lead comp.

Topotecan
Irinotecan
Hycamtin®
Campto®

N N

HO N O
O
N O O
N N
O N
O
OH O
OH O

Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

•Compounds for photodynamic therapy
Metylaminolevulinat
Metvix® PhotoCure
O NH In vivo
In vivo N
O NH2
Heme
O N HN
Slow

HO2C CO2H

Protoporphyrine IX (Pt IX)

red light
570-670 nm
Pt IX Pt IX*

O2 O2
(singlet) (triplet)

O2 OH

ROS Cell death

Tyrosine-Kinase Inhibitors
Enzyme coupled receptors - Catalytic receptors (Chapter 4)

Ligands: Peptide hormones

Growth Stimulation

1) Binding of Ligand
2) Dimerisation
of reseptor Phosphoryl of Tyr

Tyr kinase -OH -OH -OH

domain
(Janus kinase)

STATS
protein

O P O P STATS
O P O P 1) Phosphoryl. of STAT
protein
2) Release of STAT in cytoplasma
3) STATto cell nucleus
4) Intitation of transcription

Growth
Imatinib
Glivec®
Leukemia types

N
N
H H
N N N N

O N

Gefitinib
Iressa® - Not in N.
Lung cancer
Side effect: Intestinal lung disease (may be fatal)
0.3 % US
2% Japan

H3CO N

N
N O
O HN

F
Cl
•Chemotherapy
•Alkylation Agents √
•Antimetabolites / Nucleoside Analogs √
•Antibiotics √
•Antimitotic Agents √
•Micellaneous Antineoplastic Agents √
•Hormonal Therapy
Estrogens and agonists
O OH OH

H in vivo H H OH
in vivo
H H H H H H
HO HO HO

Estrone Estradiol Estriol

(Low activity) (low activity)

OH
(fast metabolism)
OH
H
OH
H H
HO
HO
HO Overlap estradiol

Diethylstilbestrol
Estrogene agonist, used as drug before

Antiestrogens
Breast cancer
Tamoxifen (estrogen depend.)
Nolvadex® Tamoxifen® N
O
 Aromatase Inhibitors
Estrogen depend. breast cancer
Inhib. estrogen biosynth.

O OH

H H 17βHSD H
H H O OH
H H H H H
HO O O
NADPH, O2
Kolesterol Antrostendion Testosteron
O O

Aromatase Aromatase - HCO2H

taut
HSD: O OH H
Hydroksystereoid dehydrogenase
H 17βHSD H HO O
H H H H
HO HO
Østron Østradiol

Exemestan Anastrosol Letrozol

Aromasin® Arimidex® Femar®
N N
N N
O N
H
N
H H N
N
O
N
N
Androgens OH OH

H H
5α-reduktase
H H H H
O O
H
Testosterone 5α-Dihydrotestosterone (5DHT)
More active

Anti-androgens
Flutamid Bicalutamid
H H HO O2
Eulexin® Flutamid® F3C N Casodex® F3C N S

Prostate cancer O2N

O Prostate cancer (less tox.) O2N
O
F

5α-Reductase Inhibitors
R 5α-reduktase
N
NADPH R
N
R'
H H
R' O R O
O NH N NH
NH
Finasterid H
H R'
Proscar® H N
H H H H
benign prostate H H HO N O N
O N H H
H