Anti-cancer Agents 11007 b%2bw Print

8/8/2019 Anti-cancer Agents 11007 b%2bw Print

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Anti-Cancer Agents

Alkylating Agents

Intercalators

Antimetabolites

Hormones/Aromatase Inhibitors

Tubilin Binding Agents

Miscellaneous

Kinase Inhibitors


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How can we target cancer cells?

Cancer cells proliferate uncontrollably. Rapid division.

Abnormal signalling pathways.

Immortality of cancer cells: apoptosis evaded. P53 gene altered.

Oxygen free environment (hypoxia) leads to anaerobic metabolism and lactic

acid formation; often cancer cell pH 6.8


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DNA Alkylators

Reactive electrophilic groups e.g. mustards to alkylate basic sites on

DNA (e.g. N-7 guanine) and to stop replication.

Chloromethine very reactive; reacts with blood, water; it is injected. N too

basic.Hence, not selective and severe side effects. Use: Hodgkins lymphoma.

NHN

N

N

H2N

NHN

N

N

H2N

N

CHCl

NH C

Cl

Cl

N+

CH

Cl

DNA

DNA

+

can react againAZIRIDINIUM ION


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Busulfan: Acts on bone marrow.

Me

MeD A

D A

D A

D A

D A

Me

doesn't work by aziridinium-type intermediate.

used for chronic granulocytic leukaemia

busulfan

resistance: removal and repair

of D A cross-links.


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Cis-platin; A very important anticancer agent

t

Cl

Cl

t

Cl

t

cis-platin

+

+

2+

H3N

Pt

NAH3N

NA

NA

2+

DNA t Pt t H NA

t t

resistance: reduced accumulation of drug: drug efflux: increased

formation of S-nucleophiles to inactivate drug.


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Alkylators: t i g thereactivity

N

Cl

Cl

HO2C

chloram ucil.

orally active

O

O

N

H2N OCH3

O

ONH2

NH

reactivea iridi e function:

activated by reduction in vivo in hypoxiccells

(solid tumours). Very toxic.

itomycin C

N

Cl

Cl

H2N

HO2C

L PAM

Basicity on reduced (due toaromaticsubstituent);

lone pair drawn back into pi system; lowerreactvity.Phenylaninerecognised and can be transported intocell by carrier proteins.


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Prodrugs

P

LLY V L LE

P G VE X

y l i

P-450 P

iver

ytotoxi g nt

eve s o phosphoramidase enzyme

e evated in tumour ce s

S

S 3-

acro ein- side e ects and toxicity

can a ky ate cysteines in proteins

mesna

added

Michae acceptor


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Other Prodrugs

O

O

O

O

isocyanate re ts th s es o rote s

trosoure s: re e se k t g ge t

e

O Pr

Pt t o

Pro r e eth d o u o

eth t g ge ts


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ADEPT (Antibody Directed Enzyme Prodrug Therapy)

Two stages:

i) antibody-enzyme administered and designed to bind to tumour.

ii) inactive, stable prodrug of cytotoxic agent added; cleaved by

enzyme/antibody (carboxypeptidase).

Toxic drug is released in tumour cell and higher concentrations can be used.

2

2

I

I

cleavage by

carboxypeptidasec x c e

R DRUG


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Exam question

(a) Name four features of cancer cells that distinguish them from healthy cells (4)

(b) Explain the terms nitrogen ustar and alkylatingagent and their uses in cancerchemotherapy. (6)

(c) Propose a mechanism of action for the following anticancer agents Thiote a andTreosulfan and explain the term ro rug: (6)

(d) Estra ustine is used for certain prostate cancers and consists of a nitrogen mustardcombined with an oestrogen moiety. Suggest a mechanism of action and the role of theoestrogen moiety. (4)

H3CO2SO

OSO2CH3

OH

HO

Treosulfan,a Prodrugof(L)-diepoxybutane

O

O

(L)-diepoxybutane

P=S

N

N

N

thiotepa

OH

O

N

Cl

Cl

O

Estramustine


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Synthesis of Alkylating Agents

H2N

CO2H

O

N

CO2H

Cl

l

i

ii SOCl2

chlo oa cil

N

Cl

l

O

Cl

l

OH

H2N

HNEt2 N

Cl

l

O

O

NH

cyclo hos ha i e


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Intercalators

Flat aromatic/heteroaromatics slip into DNA double helix and distort it;

replication/transcription enzymes inhibited.

+H3N

O

O

OH

OHO

O

R

su ar Anth y lin s . . o o u i in.

bi s t s t NA

N

HN

NHSO2Me

MeO

Acr d ne ( la ar)

N

S

S

N

O

RR'

Bl omycins

bithiazole- flat intercalator


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Topoisomerase Inhibitors/Poisons

Topo II crucial forDNA unravelling, releasing tension for replication. Cleaves

both strands ofDNA.

Elevated levels/activity of Topo II in cancer cells.

Teniposide more effective cytotoxic than etoposide; less polar and easier to

cross membranes.

O

O

Ar

O

O

O

Podophyllotoxins e.g. etoposide; =CH .

Teniposide =

OR

S

HO

HO


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Camptothecins

Topoisomerase I poison. actone group important for activity.

Camptothecin (isolated from Chinese bush) toxic with poor solubility.

Topotecan has solubilising groups; Irinotecan is a prodrug.

The Topo I enzyme can mutate- resistance to drug.

N

N

O

O

OOH

a ptothecin; 1= 2= 3= H

optotecan: 1=H, 2= H2NMe2; 3=OH

rinotecan: 1=Et; 2=H; 3=

12

3

N N

O

O

Lactonegroupcan open to le active

carbo ylategroup


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Antimetabolites

Inhibitors of enzymes used forDNA or nucleotide synthesis.

EitherDNA synthesis is blocked or abnormal DNA is made, triggering apoptosis. Methotrexate resembles folic acid and inhibits dihydrofolate reductase, involved in

DNA building block synthesis.

Other false building blocks used to stop DNA replication.

ery important, currently used line of drugs.

HN

N

N

N

HN

O

HO C

CO H

O

H N

Folic aci

N

N

N

N

MeN

O

HO C

CO H

NH

H N

et otre ate


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DNA Polymerase Inhibitors

N

N

N

N

N

F

F

N

N

NF

N

Cytara ine e cita ine e zar) Flu ara ine

N

N

DNA polymerases catalyse synthesis ofDNA using building

blocks: d TP, dCTP, dATP, dTTP.Polymerase inhibitors are phosphorylated in cells to monophosphate and act as

competitive inhibitors.

emcitabine has fewer side effects than Cytarabine; used for a range of cancers.


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Synthesis of Antimetabolites I

n

n

n

PdCl

/

-PhC

cytarabine

e

C

Cl

n

n

n

e

n

n

n

n= C

Ph ben yl rotectin ro


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Synthesis of Antimetabolites II

2

S

S

ri in for e is bon stren th

mer a to rine

fl oro ra il


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Hormones/Aromatase Inhibitors

Oestrogens used for prostate cancer; block H production/reduce testosterone

production. SERMS: Antioestrogens: tamoxifen/raloxifene for breast cancer.

Aromatase inhibitors; act on C P19/haem P450 enzyme, which catalyses

androgen to oestrogen synthesis. Use: tamoxifen resistant breast cancer: e.g.

Anastrazole.

O

Me

C

C

Ta o ifen: SE M Anastrazole

bin s to iron in hae


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Tubulin Acting Drugs

Tubulin: protein vital for cell division- polymerization/depolymerization of

microtubules.

Drugs either bind to tubulin: polymerization stopsor bind to microtubules; stabilized no depolymerization.

Cells no longer divide; mitotic spindle destroyed.

Polymerization inhibitors include :

C C

Colc c e; romsa ron and

used o rea gout;

e

Combrestatin A 4; R bus illow)

Combrestatin A 4; R os ate

re ents blood esselgrowth/angiogenisis

vinblastine, vincristine eriwinkle lant).

e 2C

C


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Miscellaneous Anticancer Targets

Matrix metalloproteases-(MMP); Zn dependant enzymes involved in cellinvasion and metastasis.

Proteasome: degrades defective (ubiquitin-labelled) proteins. Inhibitingproteasome will lead to protein overload and trigger apoptosis.

HistoneDeacetylase (HDAC):DNA wraps around histones, part of chromatin.Histone acetylase adds acetyl groups to ys residues and histone deacetylaseremoves the Ac groups-important in transcription.

Heat shock protein 90 (Hsp90); ATP dependent chaperones for proteinclients such as kinases, hormones.

Telomerase expressed in over 85% of cancers. Cancer cell can divideindefinitely.


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Thalidomide Analogues

Racemate originally used as a sedative but responsible for birth defects

when used in pregnant women- teratogenic.

Inhibits angiogenisis, promotes apoptosis.

teratogenic properties lost (NH group)

N

NH

Thali o i e

N

NH

NH

N

NH

NH

A i i e i i


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Signalling Pathway Inhibitors

Some signalling pathways are unique to cancer and selective targets

can be found. Fewer toxic side effects.

Targets include:

Farnesyl transferase (Ftase): Mutated Ras (oncogene) signalling

protein in 30% of cancers. Ras involved in cell multiplication.

Inhibitors mimic terminal tetrapeptide of Ras.

Ras

S

PP

Ras

S

Farnesyl transferase

Farnes l iphosphate

c steine resi ue

h drophobic hookfor inner surface ofcell

membrane: Ras can be involve in

transduction


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Ftase Inhibitors

onafarnib developed from a screening library.

It has no Zn-binding groups so this was incorporated in Sch 6374.

Imidazole in Sch 6374 binds to Zn; Ph (red) acts as steric shield to

prevent metabolism (Fe binding).

Bromine absent in final product- molecular weight lowered.

l

Sch 226374 0.36 M

Br

l

Br

onafarnib; I !

. n


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Protein Kinase Inhibitors

> 000 protein kinases (PKs).

PKs phosphorylate tyrosine and serine/threonine residues in proteins.

Involved in signalling pathways with hormones, growth factors.

In many cancers, PK or hormone over-active or upregulated receptor.

EGFR (Epidermal growth factor receptor)is mutated to an oncogne;

abnormal gene in brain, breast lung, GI cancers.

ATP is phosphorylating agent.

Kinase receptors possess both an ATP & substrate binding site.


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Cyclin Dependent Kinase Inhibitors (CDKIs)

Serine or threonine kinases activated by cyclins.

Inhibited by CDKIs. These compete with ATP for kinase active site.

Involved in cell cycle; over-expressed in cancer.

Inactive in normal cells so cancer drugs have fewer side effects.

e

e

Cl

e

Staurosporine Flavopiri ol oscovitine


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ATP Binding Site; Target for Kinase Inhibitors

Different kinase ATP binding sites have different

amino acid residues-selectivity of inhibitors.

EGFR receptor

P

-

P P -

--

O

eS

N

H

O

HN

O

NONH2

Gln

Leu

etibose ocket

Hy ro hobic ocket

left

etal

s

s ace variesbet een

kinases; use for kinase

inhibitor esign

Gatekeeper

residue


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Types ofEGFR Kinase Inhibitors

N

N

HN Cl

F

O

O N

O

Ire ( eftini )

N

N

HN

O

O

O

O

T rcev


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32/33

Synthesis of Iressa Analogues

"

"

"

S

#

Ar

"

Ar

Me

$

A%

Ar %

S l%

Ar

l

S& Ar

ethionine Sery nu leo hili

yr

rote tion of henol

e rote tion

r%

n%

n

e ethylation


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Gleevec: Selective AnticancerDrug

Treatment for chronic myeloid leukaemia. Caused by protein kinase Bcr-Abl.

Excessive white blood cell formation

N

NN

HN NH

O

N

NMe

Imatinib( l v c)

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Anti-cancer Agents 11007 b%2bw Print