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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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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)