Anti-cancer compounds / Antineoplastic Agents, chapter 38

Neoplasm: New and diseased form of tissue growth Benign (godartet) neoplasm: Easy to separate from surounding tissue,

no metastases

Malign (ondartet) neoplasm: Invassive to surounding tissue Metastases Cancer

Metastase: Secondary tumors, different location Malign cells separated from primary tumor

and spread by vascular- or lymph systh.

Terminology differents types of cancer confusing

Cell cycle: Proliferating cells

G1: Newly born cell Short period proliferating cells

S: Replication of DNAG2:M: Mitosis

G0: Non-proliferating cellQuiesence

Cell death

Prophase Metaphase

Anaphase Telophase

Prophase Metaphase

Anaphase Telophase

Control by growth factors

Control by growth factorsTumor

Inner part:Youngest cellsHypoxic regionNon-proliferating cells

Outer partProliferating cells

Most drugs act on cells in mitosis

DNA and DNA replicationDNA bases

Double -helix

Base pairs

HN

N

O

O

Thymin

N

N

NH2

O

Cytosin Adenine

N

N N

N

NH2

Guanine

HN

N N

N

O

H2N

DNA helicases: UnwindingDNA binding proteins: Prevents winding backDNA primase: formation of DNA/RNA primer (from free nucleosides in cell)DNA polymerase: Catalyse elongation of new strand (5’ - 3’)

Lagging strand:DNA ligase: Connects Okasaki fragments

Biochemical Basis of Cancer

•Mutation•Chemicals•Oncogenic Viruses•Altered Gene Expression

Mutation1. Mutation(s) = initiation (not cancer alone)2. Promotion; proliferation of mutated cells, exposure to chemical

(not carciogenic alone, ex estrogen)

Chemicals

Compounds (or metabolites) that reacts with DNA (alkylation agents)or initiate free radical processes that eventually damage DNA (Ex ionizing radiation)

Benzo[a]pyrene OH

HO

O

Metabolite

HN

N N

N

R

O

H2N

Guanine in DNA

HN

N N

N

R

O

HN

OHHO

HO

Biochemical Basis of Cancer

•Mutation•Chemicals•Oncogenic Viruses•Altered Gene Expression

Oncogenic VirusesViral DNA (or proviral RNA from RNA viruses) inserted in host DNA .... Mutation

Altered Gene ExpressionIncorrect expression of proto-oncogene

Increased express. oncogene - Increased prod. of growth factorsDecreased expression of tumor-supressor genes (anti-oncogenes)

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

Alkylating Agents

HN

N N

N

R

O

H2N

Guanine in DNA

R-X HN

N N

N

R

O

H2N

R

HN

N N

N

R

O

H2N

R

HN

N N

N

R

O

H2N

R

DNA Bases - Nucleophilic Centra

HN

N

O

O

Thymin

N

N

NH2

O

Cytosin Adenine

N

N N

N

NH2

Guanine

HN

N N

N

O

H2N

HN

N N

N

NMeO

Me

Br

-218.6

-214.9HN

N N

N

NMeO

Me-225.9

-136.5138140

HN

N N

N

R

O

H2N

Guanine in DNA

HN

N N

N

R

O

H2N

X X

NH

NN

N

R

O

NH2

Also O in phosphate may be alkylated

Other 7.9-Dialkylpurinium compds

N

N N

N

NH2

Me

H

(+)-Agelasine DCl

N

N N

N

CH3O CH3

NR

R'

Heteromine A: R = R' = CH3Heteromine B: R = CH3, = R' = HHeteromine C: R = R' = H

Cl

CH3

N

N N

N

O CH3

H2N

1-Methyl-herbipoline

CH3

ClH3C

N

N N

N

O CH3

H2N

Herbipoline

CH3

Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes

ClS

Cl

Sulfur mustardMustard gassYpriteWorls war I (1917)Impurity smell like mustard / garlic

ClS

NuH

ClS

Nu

+ HCl

NuHNu

SNu

+ HCl

Br

BrRSH

Br

S

S R

Nu(i.e. DNA)

Metabolism of alkyl halidesPhase II conjug. glutathion

ClN

Cl

Me

MechlorethamineFDA 1949

N

R

HN

N

NN

R

OH2NHN

N

NN

R

O NH2

ClN

Cl

R

Rel. selective tox. to lymphoid tissue(Hodkins disease, Lymphomas)

More water sol.

Tox. to rapid proliferating cells (short time for DNA repair)

ClS

Cl ClS

NuH

ClS

Nu

+ HCl

Slow

less stable than N-aanalog

Moderate

ClN

Cl ClN

NuH

ClN

Nu

+ HCl

Fast

Moderate

R

R2- order kinetics

1. order kinetics(1. step rat lim)

R=Alkyl

R

ClN

Cl ClN

NuH

ClN

Nu

+ HCl

Slow

ModeratePh

Lone pair delocalizedLess nucleophilic

Ph1. order kinetics(1. step rat lim)

ClN

Cl

POHN

O

HNCl

PON

OCl

ClN

Cl

NH2

CO2H

ClN

Cl

CO2H

L-isomerActive transport mech (L-AA)

Aryl decrease reactivity

ChlorambucilLeukeran®,

MelfalanAlkeran®,

CyclophosphamideSendoxan®

Pro-drug

IfosfamideHoloxan®

Pro-drug

ClN

Cl

POHN

OCYP450

ClN

Cl

POHN

O

HO

≈Hemiacetal

ClN

Cl

POH2N

O

O

Not nucleophiliccf amides

H

B

O

ClN

Cl

POH2N

O

Active compound

More nucøeophilicNeg charge (phys. pH)prevents delocal.

Cl

HN

Cl

MESNA Co-admin.

ClN

Cl

POHN

O

ClN

Cl

POH2N

O

OH

B

O

ClN

Cl

POH2N

O

OS

O OSH O

Activation by CYP450 (CYP3A4); enzym indusing drugs may increase activity

CYP3A4 inhibitors

Decrease activation of cyclophosfamide

O

O

O O

Flavenoid / coumarine dersee p 225

Estramustine phosphateEstracyt®

Pro-drug

O

O P

O

O

O

Na

Na

N

O

Cl

Cl

Water solubility

1) Oral absorb2) Fast metabol.

O

OH

N

O

Cl

Cl

Main comp. plasma

EstradiolCarry to cells with estrogenic receptors

Estrogenic (Anti-androgenic) effect protate cancerCleaved to active alkylating agent?

Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes

Busulfan

SO

OS

O O

O O

Not reg. NMono or dialkylationBetter leav. gr, not 3-embered ring intermedcf dimethyl sulfate

Thiotepa

P

S

N N

N

Nu

Even more reactive at low pH

P

S

N N

N

H

Not reg. N

TemozolomideTemodal®

N

NN

N

N

O

NH2

O

Hydrolysis NHHN

N

N

N

CH3

NH2

O

NH

NH2

NNH2

O

N

N

H H

N

N

H H

LomustineLomustine medac® Nitrosoureas

O

NH

NR'R

NO

O

NH

N

NO

ClWeak base

O

N N

NO

ClO

NN N O

H

NC

O

+N

N

OH

N2 OH

Reactive vinilic cation

DNA-Nu

isocyanate

H20

NH2

CO2

Alkylating Agents1) Nitrogen mustards2) Other alkylation agents3) Pt-complexes

PtH3N NH3

XX

cis

PtX NH3

XH3N

trans

Square planar Pt-complexes; Pt(II)

Pt2+

10 electrons

X

NH3NH3

X

18 electron Pt-complex

c.f. (Ph3P)2PdCl2

PtH3N NH3

XX

cis

2 DNA-Nu

PtH3N NH3

Nu-DNADNA-Nu

(Complexes with trans isomers are more readily regognized and repaired)

+ 2 Cl

NH3

PtH3N Cl

ClIntracellLow Cl-conc

H2O NH3

PtH3N OH2

Cl

+NH3

PtH3N OH2

OH2

2+

Pt(II) [as Pd(II)] electrophilicNucleophilic subst.

OPt

OPt

H H

H H

NH3

NH3

H3N

H3N

2+

Most probably

Guanine

Guanine

Guanine

Guanine PtNH3

NH3

Preferably: Binding to N7 in guanine 1,2-Intrastrand

NH3

PtH3N N

N

N

NR

HNN

O

H2N

N

HN NH2O

Guanine

Guanine PtNH3

NH3

Certain proteins binds to bent DNA, and prevents normal repair

Pt replace Zn in necessary transcription factors

DNA polymerase “collides” with Pt, DNA strain breaks mechanically

NH3

PtH3N Cl

Cl

NH3

PtH3N O

O

O

O

CisplatinPlatinol® Platistin®

CarboplatinCarboplatin® Carbosin® Paraplatin®More stabile comp. (reacts less readily with water)