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 metabolitesOften close structural similarities metabolite and antimetabolite

earlier ex. PABA / sulfonamides

H2NO

OH

PABA

H2N S

O

O

NHR

Antibact. sulfonamide

N

N NH

N

OH

H2N

NH

OH

O

Dehydropteridinsyre

N

N NH

N

OH

H2N

NH

NH

O

Dihydrofolic acid

CO2H

CO2H

N

N N

N

OH

H2N

NH

NH

O

Folic acid

CO2H

CO2H

From diet, humans

N

N NH

HN

OH

H2N

NH

NH

O

Tetrahydrofolic acide

CO2H

CO2H

Folate-reduktase

Essential processesbacteria and animalsex. Thymin synthesis(Metab. CH3OH)

Trimetoprim

N

N

NH2

H2N OCH3

OCH3

OCH3

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 BaseO

RO

POO

O

R=H in DNAR=OH in RNA

HN

N

O

O

Thymin

N

N

NH2

O

Cytosin Adenine

N

N N

N

NH2

Guanine

HN

N N

N

O

H2N

DNA

RNA HN

N

O

O

Uracil

Cytosin Adenine Guanine

5-Fluoruracil (5-FU)Fluorouracil®, Flurablastin®, HN

NH

O

O

Fin vivo

HN

N

O

O

F

O

HO

OP

O

OH

HO

InhibitorThymidylate synthetase

O

H2N OP

O

OHOH

Carbamoyl phosphate

+H2N CO2H

HO2C

Asp

HN

NH

O

O CO2H

Orotic acid

HN

N

O

O

O

HO

OP

O

OH

HO UMP

HN

NH

O

O

Uracil

More common route in cancer cells5-FU more easily activated in cancer cells (?)

HN

N

O

O

O

HO

OP

O

OH

HO

UMP

ThymidylateSynthetase

HS

NHN

NHN

N

O

NH2

R

Tetrahydrofolate

N5N10.Methylene Tetrahydrofolate

BH

HN

N

O

O

O

HO

OP

O

OH

HO

H

H

ThymidylateSynthetase

S B

NHN

NHN

NH

O

NH2

R

HN

N

O

O

O

HO

OP

O

OH

HO

H

ThymidylateSynthetase

S BH

NHN

NHN

NH

O

NH2

R

H

NHN

NHN

NH

O

NH2

R

HN

N

O

O

O

HO

OP

O

OH

HO

H

ThymidylateSynthetase

S BH

HN

N

O

O

O

HO

OP

O

OH

HO

TMP

Synth. thymine nucleotide from uracil nucleotide by thymidylate synthetase

HN

N

O

O

O

HO

OP

O

OH

HO

5-FU metabolite

ThymidylateSynthetase

HS

NHN

NHN

N

O

NH2

R

BH

HN

N

O

O

O

HO

OP

O

OH

HO

H

F

ThymidylateSynthetase

S B

NHN

NHN

NH

O

NH2

R

F

Enzyme inhibition

5-FU metabolism

Additional mechanisms: Incorp. DNA / RNA

HN

NH

O

O

F

Dihydropyrimidinedehydrogenase

HN

NH

O

O

F

H Inactive metabolite

HN

NH

O

O

Additive in some 5-FU preparates (Not in N)

HN

N

O

O

F

O

5-FU prodrug

+ HN

NH

O

O

Inhib. Dihydropyrimidinedehydrogenase

TegafurUFT®

N

N

HN

O

O

HO

F

O

O

Pro-drog 5-FU

KapecitabinXelodar®,

Cytarabine (ARA-C)Cytarabin®, Cytosar®,

N

N

NH2

O

O

HO

HO

OH

ARA-C

metabolic activation

N

N

NH2

O

O

HO

O

OH

ARA-C

PPP

Metabolic inactivation(fast)

HN

N

O

O

O

HO

HO

OH

N

N

NH2

O

O

HO

OP

OH

N

N

NH2

O

O

HO

OP

Inhib. DNA polymerase

Incorporation DNA/RNA; misreading

N

N

NH2

O

O

HO

HO

F

F

Metabolic activation (triphophate)Incorp. DNA / RNA

GemcitasbinGemzar®,

6-Mercaptopurine (6-MP)Puri-Nethol®

N

N

SH

NH

N HN

N

S

NH

N

S-Analog hypoxanthine

Metabolic activation HN

N

S

N

N

O

OHHO

OP

6-MPMPInhib. several steps in purine biosynth

N

N

S

N

N

O

OHHO

OP

Me

HN

N

S

N

N

O

OHHO

OPPP

Incorp . DNA / RNA instead og guanine

also antimetabolite

HN

N

S

NH

N

H2N

6-thioguanine (not drug in N)≈ 6-MP activity

N

N

S

NH

N

N

N

NO2

Me 6-MP pro-drugused before

O

OHHO

H

O

OP

P

O

OHHO

NH2

O

OP

P

HN

N N

N

O

OOP

OHHO

Inhib by 6-MP metabolite

HN

NH

N

N

O

OOP

OHHO

O

HN

N N

N

O

OOP

OHHO

H2N

N

N N

N

NH2

OOP

OHHO

H2N CO2H

NH2O

H2N CO2H

OHO

glutamine glutamate

N

N N

N

NH2

OHO

OH

HO

F

Antimetabolite

Not good substrate for adenosine deaminase

FludarabineFludara®

CladribinLeustatin®

N

N N

N

NH2

OHO

HO

ClNot really antimetaboliteInhib. repair enzymes

Potential Purine Antimetabolites

N

N N

N

OHO

HO

Activity various cancer cell lines Hocek et al. J. Med. Chem. 2000, 1817

OH

X

N

N N

N

OHO

HO

Activity Leukemia cellsInactive M. tub.

OH

O

Cl

Gundersen et al. J. Med. Chem. 2002, 1383

N

N N

N

O

Cl

Ph

Weak activity Leukemia cellsHIghly active M. tub.

N

N

Ph

N

N

R

R:, H, THP, Rib, Bn

More active than 6-MP and FluARALeukemia cellsBråthe et al. Bioorg. Med. Chem. Lett. 2003, 877

Folic Acid analogs as antimetabolites

MetotreksatMetoject®

RaltitrexedTomudex®

HN

N N

N

O

H2N

NH

O

NH

CO2H

CO2H

Folic acid

DHFR

HN

N NH

N

O

H2N

NH

R

Dihydrofolate

DHFR

HN

N NH

HN

O

H2N

NH

R

Tetrahydrofolate

PABA

Microorganisms

HN

N NH

N

O

H2N

N

R

Thymine synth

HN

N N

N

O

N

O

NH

CO2H

CO2H

S

N

N N

N

NH2

H2N

N

O

NH

CO2H

CO2H

Trimetoprim

N

N

NH2

H2N OCH3

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 verticilliusNaturally occuring as Cu-chelates

N N

H2N

NH

O

H2N

NH2

OH2N

O

N

O NH

NHN

NH

HN

HO

OOH

O

N S

NS

HN

O

R

Bleomycine A: R = S(CH3)3

Bleomycibe B:NH2

HN-CH2

NH2

O

O

OH

OH

HO

O

OH

OH

OH O

NH2

DNA binding

Interact heterocycl. bases

Electrostat. interact. with phosphates

N N

H2N

N

O

H2N

NH

OH2N

O

N

NHNFe

O2

1) Binds Fe(II) inside cells

2) Bleomycin complexed Fe(II) reduce O2

3) .OH radicals produced

4) Cleavage of DNA

BleomycinBleomycin Baxter®

Actinomycins

Isolated from Streptomyces sp.

Dactinomycin (Actinomycin D)Cosmegen®

O

N

O

HN O O

NH2

NH

O ONH

O

N O

N

O

O

N

O ONH

O

N O

N

O

O

N

Planar, aromatic ringsIntercalate between G-C base pairs(π−π stacking interact)

- 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

N N

CO2H

O

Parent comp.Nalidixic acid

Urinary tract infect. earliereffect on Gram-negative bacteria (ex. E. coli)

Moderne quinolones

N

O

CO2H

R

FR

R

R

F increase activity

Essentialt

Preferably HMust have aromatic ringcondenced with the pyridine

must be oxo

Chelater withCa2+, Mg2+, Zn2+, Fe2+, Fe3+, Bi3+

N

O O

O

N

OO

O

Met2+

N

O OH

O

Intramolek.H-bond

pKa ca 5.5 - 6.5(Benzoic acid pKa 4.2)

Antracyclines

Isolated Streptomyces sp, several semisynth analogs

DoxorubicinDoxorubicin® Adriamycin® Caelyx®R1 = OMe, R2 = OH, R3 = H; R4 = OH

O

O

OH

OHO

OH

O

R2

R3

R4NH2

CH3

R1

DaunorubicinCerubidin® R1 = OMe, R2 = H, R3 = H; R4 = OH

IdarubicinZavedos® R1 = H, R2 = H, R3 = H; R4 = OH

EpirubicinFarmorubicin® R1 = OMe, R2 = OH, R3 = OH; R4 = H

O

O

OH

OHO

OH

O

OCOC4H9

HOHN

CH3

OCH3

COCF3

Valrubicin

O

O

HN

HNOH

OH

HN

OH

NH

OH

MitoxantroneNovantrone®

O

OH

NHR2

O

N

OHHOOOH

R6

H HR5

Antibacterial Tetracyclines

Mechanism ≈ Actinomycins (Intercalation)

Also interact aminosugar - phosphate

Antraquinone - red/ox react: prod. reactive oxygen radicals

DNA-Daunomycin Complex

MitomycinsIsolated Streptomyces sp,

O

O

N

H2N

H3C

OCH3

NH

OCONH2

red

OH

N

H2N

H3C

OCH3

NH

OCONH2

quinone Hydroquinone

OH

OH

N

H2N

H3C NH

OCONH2

HB

O

OH

N

H2N

H3C NH

OCONH2

H B

H

O

OH

N

H2N

H3CNH2

OCONH2

In vivo:

Active drug

DNANu

H

OH

OH

N

H2N

H3CNH2

O

DNANu

ONH2

Nu NuOH

OH

N

H2N

H3CNH2

DNANu

Nu

OH

OH

N

H2N

H3CNH2

DNANu

Nu

Mitomycin CMutamycin®

ConformycinsIsolated Streptomyces sp,

Ex. transition state analogs

N

N N

N

NH2

OHO

OHHO

Adenine

Adenosine deaminase

HN

N N

N

H2N

OHO

OHHO

OH

HN

N N

N

OHO

OHHO

O

Inosine

Also metab. of anticancer / antiviraladeninederiv.

N

NH

N

NBn

OBn

CF3

Geir AndresenCytotox.

N

N

OHO

RHO

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

HN

OH

sp3

•Chemotherapy

•Alkylation Agents √

•Antimetabolites / Nucleoside Analogs √

•Antibiotics √

•Antimitotic Agents

•Micellaneous Antineoplastic Agents

•Hormonal Therapy

Prophase Metaphase

Mitosis

Anaphase Telophase

Antimitotic agents bind to microtubuli

Supression of microtubuli dynamics

Metaphase arrest

Vinca alkaloids

Vinca alkaloids (Indols)from Vinca rosea(Catharantus roseus)MadagaskarPerivinkle

NH

N

HO

MeO2C

MeON

R

N

H OCOMe

CO2MeOH

R=-Me: Vinblastin, Velbe®R=-CHO: Vinkristin, Vincristine®

NH

N

MeO2C

MeON

CH3

N

H OCOMe

CO2MeOH

Vinorelbine, Navelbine®

Binds to microtubuli- Supression of microtubuli dynamics-Metaphase arrest

Depolymerization of microtubuli high conc.

Taxanes

First isolated from bark of Western / Pacific yew (Taxus brevifolia)NIH screening of plant extracts 1960s

Mecanism ≈ Vinca alkaloids, different binding sites

R1 = -Ph, R2 = -COMe: Palitaxel, Taxol®R1 = -OBut, R2 = -H: Dodetaxel, Taxotere® Semisynthetic

O

O

HO

OH

R2

OO

HO

O

O

HO

NH

OR1

O

O

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

O

HO

OH

R2

OO

HO

O

O

HO

NH

OR1

O

O

O

OH

HO

OH

OO

HO

HO

O

O

Deacetylbaccatine III

(-Total syntheses)

Colchicine

From Meadow-saffron, Colchicum autumnale (Tidløs) seedsBinds to microtubuli - metaphase arrest, too toxic too be used in cancer treatmentUsed to treat gout (podagra)

H3CO

CH3O

H3CO

O

OCH3

NH

O

Comming next? - Epothilones

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

O

OHO

N

S

OOH

O

Epothilone B

O

OHO

N

S

OH

O

Epothilone A

O

OHO

N

S

OOH

Epothilone C

O

OHO

N

S

OOH

Epothilone D

O

OHO

N

S

OH

O

Epothilone E

OH

O

OHO

N

S

OOH

O

Epothilone F

OH

•Chemotherapy

•Alkylation Agents √

•Antimetabolites / Nucleoside Analogs √

•Antibiotics √

•Antimitotic Agents √

•Micellaneous Antineoplastic Agents

•Hormonal Therapy

•Hydroxyurea•Podophyllotoxines•Camptothecins•Compounds for photodynamic therapy•Tyrosine-Kinase Inhibitors

O

H2N NH

OH Hydroxykarbamid®

Inhib. ribonucleotide diphosphate reductaseArrest cells in G1-S interphase (combi with radiation)

PodophyllotoxinesFrom Podophyllum peltarumMay apple

Antiviral, veneric warts

Toxic - lead for anticancer drugs

O

OO

OHOMeMeO

O

Etoposide

O

O O

HO

HO

O

OO

OMe

OMeMeO

OH

O

Podophyllotoxin

EtoposideEposin® Etopofos® Vepesid®

Affects DNA topoisomerase II (not intercalating)DNA strand breakage

Camptothecins

First isolated Camptotheca acuminata (Chinese tree)NIH screeningLater found in several plants

N

N

O

O

OOH

Camptothecin, toxic, Lead comp.

N

N

O

O

OOH

HO

N

N

N

O

O

OOH

O

N O

N

TopotecanHycamtin®

IrinotecanCampto®

Semisynth. inhib. DNA topoisomerase II, DNA strand breakage

•Compounds for photodynamic therapy

MetylaminolevulinatMetvix® PhotoCure

O NH2

O

OIn vivo In vivo

Slow

Heme

Protoporphyrine IX (Pt IX)

N HN

NNH

HO2C CO2H

ROS Cell death

Pt IX

red light570-670 nm

Pt IX*

O2(triplet)

O2(singlet)

O2 OH

Tyrosine-Kinase Inhibitors

Enzyme coupled receptors - Catalytic receptors (Chapter 4)

Ligands: Peptide hormones

Growth Stimulation

1) Binding of Ligand2) Dimerisation of reseptor

-OH -OH -OHTyr kinasedomain(Janus kinase)

Phosphoryl of Tyr

O P O P

STATSprotein

O P O P STATSprotein 1) Phosphoryl. of STAT

2) Release of STAT in cytoplasma3) STATto cell nucleus4) Intitation of transcription

Growth

ImatinibGlivec®Leukemia types

GefitinibIressa® - Not in N.Lung cancerSide effect: Intestinal lung disease (may be fatal)

0.3 % US 2% Japan

HN

HN

N

N

N

O

N

N

O

N ON

N

HN

F

Cl

H3CO

•Chemotherapy

•Alkylation Agents √

•Antimetabolites / Nucleoside Analogs √

•Antibiotics √

•Antimitotic Agents √

•Micellaneous Antineoplastic Agents √

•Hormonal Therapy

Antiestrogens

HO

H

HH

O

Estrone

in vivo

HO

H

HH

Estradiol

OH

HO

H

HH

Estriol

OH

in vivo

(Low activity)

(fast metabolism)

OH

(low activity)

ON

TamoxifenNolvadex® Tamoxifen®

HO

OH

DiethylstilbestrolEstrogene agonist, used as drug before

HO

H

HH

OH

HO

OH

Overlap es tradio l

Estrogens and agonists

Breast cancer(estrogen depend.)

Aromatase Inhibitors

Estrogen depend. breast cancerInhib. estrogen biosynth.

HO

H

HH

Østron

O

HO

H

HH

Koles tero l

H

HH

O

O

Antrostendion

H

HHO

Testosteron

OH

HO

H

HH

Østradiol

OH

AromataseAromatase

17βHSD

17βHSD

HSD: Hydroksystereoid dehydrogenase

O

NADPH, O2

O

O OHH

- HCO2H

O

Htaut

HO

H

HH

O

O

ExemestanAromasin®

AnastrosolArimidex®

LetrozolFemar®

N

N

NNN

NNN

N

N

AndrogensH

HH

O

Testosterone

OH

5α-reduktaseH

HHO

5α-Dihydrotestosterone (5DHT)More active

OH

H

Anti-androgens

FlutamidEulexin® Flutamid®Prostate cancer

F3C

O2N

HN

O

BicalutamidCasodex®Prostate cancer (less tox.)

F3C

O2N

HN

O

HO O2S

F

FinasteridProscar®benign prostate

5α-Reductase Inhibitors

H

HHNH

O

ONH

5α-reduktaseNADPHN

R

R'H H

H

HHNH

HO

ONH

NR

R'

H

HHNH

O

ONHN

N

R

R'