Medicinal chemistry of anticancer drugs ppt

Introductory lecture PowerPoint slides

1. Medicinal chemistry of
anticancer drugs
Bruhan Kaggwa
Department of Pharmaceutical Chemistry
School of Pharmacy
Makerere University, Uganda

2. Reference books
Organic medicinal and Pharmaceutical Chemistry; 12
th
edition
John M. Beale, Jr. and John H Block
FOYE’s principles of medicinal chemistry; 6
th
Edition
Thomas L. Lemke et al
An Introduction to Medicinal Chemistry; 5
th
Edition
Graham L. Patrick

3. General classification of anticancer drugs
DNA cross linking agents (Alkylators and organic metallics)
Nitrogen mustards and Aziridinemediated Alkylators
Nitrosoureas
Procarbazine and triazenes
Miscellaneous alkylating agents
Organoplatinumcomplexes
Antibiotics
Anthracyclines and anthracenediones
Miscellaneous anticancer antibiotics
Antimetabolites
Pyrimidine antagonists: dTMP synthesis inhibitors

4. General classification of anticancer drugs
Antimetabolites
Pyrimidine antagonists: dTMP synthesis inhibitors
Direct inihibitorsof thymidylate synthase
Indirect inhibitors thymidylate synthase
Prolineantagonists; Amidophosphoribosyl transferase inhibitors
DNA polymerase/DNA chain elongation inhibitors
Miscellaneuosantimetabolites; pentostatin, hydroxyurea
Mitosis inhibitors
Taxanes
Vincaalkaloids
Topoisomerase poisons
Camptothecins
Epipodophyllotoxins

5. General classification of anticancer drugs
Miscallaneuosanticancer agents
DNA demethylators
Hormone therapy
Corticosteroids, estrogens, progestins, androgens
Luteinizing hormone releasing hormone agents
Antiestrogens
Antiandrogens
Aromatase inhibitors

6. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Alkylating agents are highly electrophilic compounds that react with nucleophilic groups
(particularly, but not exclusively, the N-7 of guanine) on DNA to form strong covalent bonds.
Alkylation converts the base to an effective leaving group so that attack by water leads to
depurination and the loss of genetic information if the resulting depurination is not repaired by the
cell.
Other nucleophilic sites on DNA susceptible to alkylation include;(N-2, N-3 of guanine, N-1, N-3,
and N-7 of adenine, O–6 of thymine, N-3 of cytosine).

7. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Some DNA alkylating agents, such as the nitrogen mustards and nitrosoureas, are bi functional ,
meaning that one molecule of the drug can bind two distinct DNA bases.
Most commonly, the alkylated bases are on different DNA molecules, and inter-strand DNA cross-linking through
two guanine N7 atoms results.
The DNA alkylating antineoplastics are not cell -cycle specific, but they are more toxic to cells in
the late G1 or S phases of the cycle.
This is the time when DNA is unwinding and exposing its nucleotides, enhancing the chance that vulnerable DNA
functional groups will encounter the electrophilic antineoplastic drug and launch the nucleophilic attack that leads
to its own destruct ion.
The DNA alkylators have a great capacity for inducing both mutagenesis and carcinogenesis; in
other words, they can promote cancer in addition to treating it.
Organometallic antineoplastics also cross-link DNA, and many do so by binding to adjacent
guanine nucleotides, called diguanosine dinucleotides, on a single strand of DNA.
This leads to intrastrand DNA cross-linking. The anionic phosphate group on a second strand of DNA stabilizes
the drug-DNA complex and makes the damage to DNA replication irreversible.
Some organometallic agents also damage DNA through interstrand cross-l inking.

8. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrogen Mustards
Are dialkylating agents i.e. one mustard molecule can alkylate two nucleophiles
MOA
1. Acid–base reaction to release the lone pair of electrons on nitrogen
2. The lone pair on N displaces the chloride to give the highly reactive aziridinium cation.
3. Nucleophilic attack (by DNA, protein etc) can then occur at the aziridinium carbon to relieve the small ring strain
and neutralize the charge on nitrogen. This process can then be repeated provided a second leaving group is
present.

9. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrogen Mustards-chlormethine

10. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrogen Mustards
Structure–activity relationships
The structure of nitrogen mustards differs only in the nature of the third group (R) attached to the amino nitrogen.
This group, which can be either aliphatic or aromatic, is the prime determinant of chemical reactivity, oral
bioavailability, and the nature and extent of side effects.
Aliphatic groups like push electrons to the N thus increasing the rate of formation and reactivity of the aziridinium
ion; Mechlorethamine reacts with water, blood, and tissues. It is too reactive to survive the oral route and has to be
administered intravenously.
Aromatic nitrogen substituent (e.g., phenyl ) stabilize the N lone pair of electrons through resonance. Resonance
delocalization significantly slows the rate of intramolecular nucleophilic attack, aziridinium ion formation, and DNA
alkylation.
Aromatic mustards have a reactivity sufficiently control led to permit oral administration and attenuate the severity
of side effects. The higher stability also provides the chance for enhanced tissue selectivity by giving the intact
mustard time to reach malignant cells before generating the electrophilic aziridinium ion.

11. Alkylation agents
Nitrogen Mustards
SARs
Aliphatic R groups
Push electrons to the N
E.g. Mechlorethamine
More reactive
Too toxic for oral use
Direct injection into the tumor
Extravasation is a common
Antidote is sodium thiosulphate
Aromatic R groups
E.g. melphalan
Stabilize N by resonance
Reduce rate of aziridinium ion
formation
Less reactive
Less toxic
Can be administered orally
DNA cross linking agents (Alkylators and organic
metallics

12. Alkylation agents
Nitrogen Mustards
Inactivation of Mechlorethamine
treatment of extravasation with sodium
thiosulphate
DNA cross linking agents (Alkylators and organic
metallics

13. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrogen Mustards
Activation of cyclophasmide
Acroleinis renotoxicmetabolite
Toxicity can be treated with MESNA
MESNA has SH groups

14. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrogen Mustards
Activation of cyclophasmide
Acroleinis renotoxic
Toxicity can be treated with MESNA
MESNA has SH groups
Other drugs
Chlorambucil
Melphalan
Estramustine
Ifosfamide
Thiopeta

15. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Nitrosoureas
These compounds are reasonably stable at pH4.5 but undergo both acid and base catalyzed decomposition at
lower and higher pH, respectively.
Decomposition leading to Alkylation of DNA involves abstraction of the NH proton, which is relatively acidic (pKa8–
9), followed by rearrangement to give an isocyanate and a diazohydroxide.
The diazohydroxide, upon protonation followed by loss of water, yields a diazo species that decomposes to a
reactive carbocation.
The isocyanate functions to carbamylateproteins and RNA, whereas the carbocation is believed to be the agent
responsible for DNA alkylation.
Alternative mechanisms of decomposition have also been proposed involving formation of chlorovinylcarbocations.
In those cases where there is a chloroethylmoiety attached to the N-nitrosourea functionality, crosslinking of DNA occurs.
Alkylation occurs preferentially at the N-7 position of guanine with minor amounts of alkylation at guanine O-6.
Drugs include;
Carmustineand Lomustine
Streptozocin

16. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Activation of Nitrosoureas-MOA
Diazohydroxide isocyanate
reactive carbocation

17. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Activation of Nitrosoureas-MOA
Diazohydroxidereactive carbocation

18. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Detoxification of Nitrosoureas
Detoxification pathways of the nitrosoureas are also possible and can play a role in resistance to this group of
agents.
Two major routes of inactivation have been identified and are indicated.
The first of these involves dechlorination, which is facilitated by CYP participation and involves cyclization to give 4,5-
dihydro-[1,2,3]oxadiazoleand the isocyanate, which is still capable of carbamylatingproteins.Theoxadiazolecan be
further degraded by hydrolysis to give several inactive products.
The second route involves denitrosation, which in the case of carmustinehas been shown to be catalyzed by CYP
monooxygenases and glutathione-S-reductase

19. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Procarbazine, dacarbazine, and temozolomide
Dacarbazineand procarbazineare prodrugs which generate a methyldiazonium ion as the alkylating agent.
Dacarbazineis activated by N -demethylation in the liver—a reaction catalysedby cytochrome P450 enzymes.
Formaldehyde is then lost to form a product which spontaneously degrades to form 5-aminoimidazole-4-
carboxamide (AIC) and the methyldiazonium ion.
Reaction of the methyldiazonium ion with RNA or DNA results in methylation, mainly at the 7-position of guanine.
DNA fragmentation can also occur.
Temozolomidealso acts as a prodrug and is hydrolysed
in the body to form MTIC (5-(3-methyltriazen-1-
yl)imidazole-4-carboxamide), which decomposes like
dacarbazineto form the methyldiazonium ion. The O6
oxygen atom of guanine groups is
particularly methylated by this agent.

20. DNA cross linking agents (Alkylators and organic
metallics
Alkylation agents
Busulfan
Chemically, busulfanis classified as an alkyl sulfonate.
MOA
One or both of the methylsulfonateester moieties can be displaced by the nucleophilic N7 of guanine, in an SN2 reaction,
leading to monoalkylatedand cross-linked DNA.
The extent of alkyl sulfonate–mediated DNA interstrand cross-linking is proportional to the length of the alkyl chain
between sulfonate esters.
tetramethylene-containing busulfanshows less interstrand cross-linking capability than hexamethylene, methylene,
or octamethyleneanalogues.
Intrastrand cross-linking also occurs, preferentially at 5′-GA-3′ but also at 5′-GG-3′ sequences. Alkylation of Cyssulfhydryl
groups is yet another mechanism of cytotoxicity.

21. DNA cross linking agents (Alkylators and organic
metallics
OrganoplatinumComplexes
Structure and MOA
The structure consists of a central platinum atom, covalently linked to two chlorosubstituents, while the two ammonia
molecules act as ligands.
The overall structure is neutral and unreactive. Once cisplatin enters cells, however, it enters an environment which has
a low concentration of chloride ions.
This leads to aquationwhere the chlorosubstituents of cisplatin are displaced by neutral water ligands to give reactive,
positively charged species which act as metallating agents.
These bind strongly to DNA in regions containing adjacent guanine units, forming covalent Pt-DNA links within the same strand
(intrastrand cross-linking).
It is likely that this takes place to the N-7 and O-6 positions of adjacent guanine molecules.
The hydrogen bonds that are normally involved in base-pairing guanine to cytosine are disrupted by the cross-links, leading to
localized unwinding of the DNA helix and inhibition of transcription.
Like nitrogen mustards, organoplatinumcomplexes are bi functional and can accept electrons from two DNA
nucleophiles.
Intrastrand cross-links most frequently occur between adjacent guanine residues referred to as diguanosine
dinucleotides (60–65%) or adjacent guanine and adenine residues (25–30%).
Interstrand cross-linking, which occurs much less frequently (1–3%), usually involves guanine and adenine bases

22. Antibiotic anticancer drugs
There are several mechanisms by which these agents target DNA, including intercalation,
alkylation, and strand breakage either directly or as a result of enzyme inhibition.
Many of the antineoplastic antibiotic compounds inhibit topoisomerase II, an enzyme responsible for maintaining proper
DNA structure during replication and transcription to RNA.
Yet another proposed mechanism of cytotoxic act ion is the generation of cytotoxic free radicals that cause single-strand
breaks in DNA
Anthracyclines and Anthracenediones
Anthracyclineantineoplastic antibiotics are very closely related to the tetracycline antibacterials.
Structurally, they are glycosides and contain a sugar portion (L-daunosamine) and a nonsugarorganic portion.
The nonsugarportion of glycosides is generically referred to as an aglycone. In anthracyclines, the aglyconemoiety is
specifically called anthracyclinoneor anthroquinone.

23. Antibiotic anticancer drugs
Anthracyclines and Anthracenediones
MOA
1. DNA intercalation
The anthracyclinoneportion of the structure, is large and predominantly
aromatic.
This flat ring system slides between the two DNA strands, orienting itself
in a perpendicular fashion relative to the long axis of DNA.
Once intercalated, the anthracycline-DNA complex is stabilizedthrough
vanderWaals, hydrophobic, and hydrogen bonds. Binding is best in DNA
regions that are rich in guanine and cytosine bases.
The protonated 3′-amino group on the daunosaminesugar has long been
thought to stabilize the intercalated complex through interaction with an
anionic DNA phosphate or covalently to the C2-NH2 of guanine via a
methylene bridging unit provided by formaldehyde.

24. Antibiotic anticancer drugs
Anthracyclines and Anthracenediones
MOA
2. topoisomerase II inhibition
Even though DNA intercalation is required before the antineoplastic action of the anthracyclinescan be realized, it
alone does not kill the cell .
Rather, the predominant cytotoxic effect is topoisomerase II inhibition.
Anthracyclines bind to the DNA-enzyme complex in the area close to the DNA cleavage site. They stabilize a
ternary cleavable complex that al lows the DNA to be cut and covalently linked to topoisomerase Tyr residues but
that does not permit the cleaved DNA to reseal .
The aromatic portion of the anthracyclinonering system and the daunosaminesugar bind to DNA, whereas the
anthracyclinoneA ring is believed to bind with the topoisomerase II enzyme.

25. Antibiotic anticancer drugs
Anthracyclines and Anthracenediones
Cardiotoxicity
Anthracyclines undergo redox cycling to prodcuce; notably, daunorubicinand doxorubicin. Newer derivatives,
idarubicinand epirubicinare less susceptible.
The C ring of the anthracyclinesissubject to a one or two electron reduction by several different enzymes
including NAD(P)H-oxidoreductases and CYP reductases to give the semiquinoneor hydroquinone.
This may undergo reversion to the starting quinonein futile redox cycling accompanied by the production of
superoxide radical. The radical is normally converted to H
2O
2by superoxide dismutase and H
2O
2is then
converted to H
2O and O
2by catalase.
However, the production of superoxide (O
2
-
) is also associated with the release of iron from intracellular stores,
which may be chelated by the anthracycline.
The iron then diverts the normal detoxification pathway by catalase so that more potent radicals such as hydroxyl
radical (
.
OH) are produced.
Myocardial cells possess lower levels of catalase and therefore are less able to detoxify the H
2O
2that results from
redox cycling. This results in increasing levels of
.
OHfor which a detoxification pathway does not exist and
therefore cellular damage occurs.
Hydroxyl radicals cause single-strand breaks in DNA, which would activate p53 and enhance apoptosis in cardiac
cells.

26. Antibiotic anticancer drugs
Anthracyclines
Cardiotoxicity

27. Antibiotic anticancer drugs
Dactinomycin
Dactinomycinbinds noncovalentlyto double-stranded
DNA by partial intercalation between adjacent
guaninecytosinebases resulting in inhibition of DNA
function.
The structural feature of dactinomycinimportant for its
mechanism of cytotoxicity is the planar phenoxazonering,
which facilitates intercalation between DNA base pairs.
The peptide loops are located within the minor groove and
provide for additional interactions.
The preference for GpCbase pairs is thought to be partly
related to the formation of a hydrogen bond between the
2-amino groups of guanine and the carbonyls of the L-
threonine residues.
Additional hydrophobic interactions and hydrogen bonds
are proposed to form between the peptide loops and the
sugars and base pairs within the minor groove.
In all, actinomycinD spans four to five DNA base pairs.
This results in high affinity with the molecule only slowly
dissociating from DNA

28. Antibiotic anticancer drugs
Bleomycins
Complex natural products isolated from
Streptomyces verticillus
MOA
The bithiazolering system which intercalates with
DNA.
Once the structure has become intercalated, the
nitrogen atoms of the primary amines, pyrimidine
ring, and imidazole ring chelate a ferrous ion
which then interacts with oxygen and is oxidized
to a ferric ion, leading to the generation of
superoxide or hydroxyl radicals.
These highly reactive species abstract hydrogen
atoms from DNA, which results in the DNA strands
being cut—particularly between purine and
pyrimidine nucleotides.
Bleomycinalso appears to prevent the enzyme
DNA ligase from repairing the damage caused.

29. Antimetabolites
Antimetabolites stop the de novo synthesis of DNA by inhibiting the formation of the
nucleotides that make up these life-sustaining polymers.
The rate-limiting enzymes of nucleotide biosynthesis often are the primary target for the
antimetabolites, because inhibition of this key enzyme is the most efficient way to shut down any
biochemical reaction sequence.
Antimetabolites also are capable of inhibiting other enzymes required in the biosynthesis of DNA,
and many can arrest chain elongation by promoting the incorporation of false nucleotides into the
growing DNA strand.
The antimetabolites serve as false substrates for critical nucleotide biosynthesis enzymes. These
enzyme inhibitors are structurally “dolled up” to look like a super attractive version of the normal
(endogenous) substrate.
They entice the enzymes to choose them over the endogenous substrate, and once they do, the antimetabolites
bind them irreversibly.
If the building block nucleotides cannot be synthesized, then DNA synthesis (and tumor growth) is stopped dead in
its tracks. If tumor growth is arrested, then metastasis slows, and the patient has a fighting chance for remission
and/or cure.

30. Antimetabolites
Antimetabolite antineoplastics are categorized by the class of nucleotide they inhibit;
Purine antagonists
inhibit the synthesis of the purine-based nucleotides adenylate monophosphate (AMP) and
guanylatemonophosphate(GMP),
Pyrimidine antagonists
Stop the production of the pyrimidine-based nucleotides, primarily deoxythymidinemonophosphate (dTMP).
E.g folate antagonists

31. Antimetabolites
Pyrimidine Antagonists:
Dihydrofolate reductase inhibitors
Dihydrofolate reductase ( DHFR ) is an enzyme which is
crucial in maintaining levels of the enzyme cofactor
tetrahydrofolate (F H4 ).
Without this cofactor, the synthesis of the DNA building
block (dTMP) would grind to a halt, which, in turn, would
slow down DNA synthesis and cell division.
The enzyme catalysesthe reduction of the vitamin folic
acid to FH 4 in two steps via dihydrofolate( FH 2 ).
Once formed, FH 4 picks up a single carbon unit to form N
5
,N
10
-methylene FH4 , which then acts as a source of one-
carbon units for various biosynthetic pathways, including
the methylation of deoxyuridinemonophosphate (dUMP) to
form deoxythymidinemonophosphate (dTMP).
N
5
,N
10
-methylene FH4 is converted back to FH 2 in the
process and dihydrofolatereductase is vital in restoring the
N
5
,N
10
-methylene FH4 for further reaction.

32. Antimetabolites
Pyrimidine Antagonists:
Inhibitors of thymidylate synthase
Methotrexate has an indirect effect on thymidylate
synthase by lowering the amount of N
5
,N
10
-methylene
FH4 cofactor required.
5-Fluorouracil is an anticancer drug which inhibits this
enzyme directly.
5-Fluorouracil is converted in the body to the fluorinated
analogue of 2′-deoxyuridylic acid monophosphate
(FdUMP) which then combines with the enzyme and the
cofactor., this terminates DNA synthesis.
Capecitabineis a prodrug for 5-fluorouracil.

33. Antimetabolites
Purine Antagonists:
Inhibitors of ribonucleotide reductase
Ribonucleotide reductase is responsible for the conversion of ribonucleotide diphosphates to
deoxyribonucleotidediphosphates.
The enzyme contains an iron cofactor which is crucial to the reaction mechanism.
This involves the iron reacting with a tyrosine residue to generate and stabilize a tyrosine free radical, which
then abstracts a proton from the substrate and initiates the reaction mechanism. Hydroxycarbamideis a
clinically useful agent which inhibits the enzyme by destabilizing the iron center.

34. Antimetabolites
Inhibitors of adenosine deaminase
Ribonucleotide reductase is inhibited directly by hydroxycarbamide, but it can also be inhibited indirectly by
increasing the level of natural allosteric inhibitors such as dATP.
The enzyme adenosine deaminase catalysesthe deamination of adenosine to inosine
Inhibition of the enzyme leads to a build-up of dATP in the cell, which, in turn, inhibits ribonucleotide reductase.
pentostatinis a natural product isolated from Streptomyces antibioticus, and is a powerful inhibitor of adenosine
deaminase.

35. Antimetabolites
Inhibitors of adenosine deaminase
Ribonucleotide reductase is inhibited directly by hydroxycarbamide, but it can also be inhibited indirectly by
increasing the level of natural allosteric inhibitors such as dATP.
The enzyme adenosine deaminase catalysesthe deamination of adenosine to inosine
Inhibition of the enzyme leads to a build-up of dATP in the cell, which, in turn, inhibits ribonucleotide reductase.
pentostatinis a natural product isolated from Streptomyces antibioticus, and is a powerful inhibitor of adenosine
deaminase.
It acts as a transition-state inhibitor, mimicking the proposed tetrahedral nature of the transition state, which is believed to
be similar to the tetrahedral intermediate.

36. Antimetabolites
Inhibitors of DNA polymerases
DNA polymerases catalysethe synthesis of DNA using the four deoxyribonucleotidebuilding
blocks dATP, dGTP, dCTP, and dTTP.
The anticancer drug cytarabineis an analogue of 2′ deoxycytidine and acts as a prodrug.
It is phosphorylated in cells to the corresponding triphosphate ( ara-CTP ) which acts as a competitive inhibitor.
In addition, ara-CTP can act as a substrate for DNA polymerases and become incorporated into the growing
DNA chain. This can lead to chain termination or prevent replication of the modified DNA.
Gemcitabine is an analogue of cytarabinewith fewer side effects.
The purine analogue fludarabineis also metabolized to a triphosphate and has the same
mechanism of action as cytarabine.
It, too, inhibits transcription and can be incorporated into RNA.

37. Antimetabolites
Purine antagonists;Amidophosphoribosyl
Transferase Inhibitors
The thiopurines6-mercaptopurine and 6-
tioguanine are prodrugs which are converted to
their corresponding nucleoside monophosphates
by cellular enzymes.
The monophosphates then inhibit purine
synthesis at a number of points.
They are also incorporated into RNA and DNA,
leading to complex effects which end in cell
death.
Both agents are converted to a common product (
thio-GMP ) which is subsequently converted to
thio-GTP and thio-dGTP, before incorporation
into RNA and DNA respectively.

38. Mitosis inhibitors
Tubulin inhibitors
Tubulin is a structural protein which is crucial
to cell division. The protein acts as a building
block for microtubules which are polymerized
and depolymerized during cell division.
Drugs can block this process:
by either binding to tubulin to prevent
polymerization
or binding to the microtubules to prevent
depolymerization.
Agents which inhibit tubulin polymerization
Vincristine , vinblastine , vindesine, and
vinorelbineare alkaloids derived from the
Madagascar periwinkle plant ( Catharanthus
roseus), and can bind to tubulin to prevent
polymerization.
Podophyllotoxinforms a complex with tubulin and
prevents the synthesis of microtubules, just like
colchicine Colchicine

39. Mitosis inhibitors
Tubulin inhibitors
Agents that inhibit tubulin depolymerization
Paclitaxel (Taxol) and the semi-synthetic analogue docetaxel are important anticancer agents that inhibit tubulin
depolymerization.
The binding of paclitaxel accelerates polymerization and stabilizes the resultant microtubules, which means that
depolymerizationis inhibited.
As a result, the cell division cycle is halted.
The benzoyl and acetyl substituents, at positions 2 and 4, respectively, play an important role in this binding interaction,
as do the side chain and the oxetanering.

40. Mitosis inhibitors
Topoisomerase Poisons
Epipodophyllotoxinse.g etoposide and teniposide
The epipodophyllotoxinsare semisynthetic glycosidicderivatives of podophyllotoxin. Although these compounds are
capable of binding to tubulin and inhibiting mitosis, their primary mechanism of antineoplastic action is poisioning
topoisomerase II, just like the anthracyclineantibiotics.
Once bound, the toxins stabilize the cleavable ternary drug-enzyme-DNA complex, stimulating DNA ligation but
inhibiting resealing. The DNA-topoisomerase fragments accumulate in the cell, ultimately resulting in apoptosis.
The RNA transcription processes also are disrupted by the interaction of epipodophyllotoxinswith topoisomerase IIα.
The drugs show selectivity for cancer cells, despite the fact that topoisomerase II is present in both cancer cells and
normal cells. This is thought to be a result of elevated enzyme levels or enzyme activity in the cancer cells.

41. Mitosis inhibitors
Topoisomerase Poisons
Camptothecinse.g Camptothecin
Camptothecinis a naturally occurring cytotoxic alkaloid which was extracted from Camptothecaacuminate.
It targets the complex between DNA and topoisomerase I
This leads to DNA cleavage and cell death if DNA synthesis is in progress, but it has been observed that these
agents are also toxic to cancer cells which are not synthesizing new DNA.
This is due to an alternative mechanism of action—possibly the induction of destructive enzymes such as serine
proteases and endonucleases.
The camptothecinsshow selectivity for cancer cells over normal cells when the cancer cells in question show
higher levels of topoisomerase I than normal cells.

42. Hormone therapy
Hormone-based therapies are used for cancers which are hormone dependent. If the cancer cell
requires a specific hormone, then a hormone can be administered which has an opposing effect.
Alternatively, hormone antagonists can be used to block the action of the required hormone.
Steroid hormones combine with intracellular receptors to form complexes that act as nuclear
transcription factors . In other words, they control whether transcription takes place or not.
Glucocorticoids, estrogens, progestins, and androgens
Glucocorticoids include prednisolone and prednisone. Prednisone acts as a prodrug and is converted enzymatically to
prednisolone in the body.
Estrogens inhibit the production of luteinizing hormone ( LH ) and, by doing so, decrease the synthesis of testosterone.
The most commonly used agents are ethinylestradioland diethylstilbestrol. Fosfestrolis the diphosphate prodrug of diethylstilbestrol.
Progestinsused as anticancer agents include medroxyprogesterone acetate and megestrolacetate.
Androgens are thought to suppress production of LH, resulting in a decrease in estrogen synthesis; these include fl
uoxymesterone and testosterone propionate (prodrug which is converted to dihydrotestosterone)

43. Hormone therapy
Glucocorticoids, estrogens, progestins, and androgens

44. Hormone therapy
Luteinizing hormone-releasing hormone agonists
Luteinizing hormone-releasing hormone ( LHRH ) is a decapeptidehormone which binds to receptors on anterior
pituitary cells and stimulates the release of LH.
On long-term exposure to LHRH, the receptor becomes desensitized leading to a drop in LH levels. Since LH stimulates
the synthesis of testosterone, this results in lowered testosterone levels.
Leuprolide and goserelin, are both decapeptideanalogues of LHRH designed to be more resistant to peptidase
degradation.
This normally takes place next to glycine at position 6 and replacing this amino acid with an unnatural D-amino
acid makes this region unrecognizable to the enzyme. Substitution of the glycine residue at position 10 with a
suitable group also increases receptor affinity.

45. Hormone therapy
Anti-estrogens
Tamoxifen and raloxifeneare synthetic
agents which antagonize estrogen
receptors and prevent estradiol from
binding.

46. Hormone therapy
Anti-androgens
Flutamideand cyproteroneacetate are used to treat prostate cancer and work by blocking the action of androgens at
their receptors.
Abirateroneis a potent and selective inhibitor of 17α-hydroxylase-17(20)-lyase,a cytochrome P450 enzyme which is
involved in the biosynthesis of androgens; the pyridine ring plays a key role in its action by interacting with the iron of
haemin the enzyme's active site.

47. Hormone therapy
Aromatase inhibitors
Aromatase is a membrane-bound enzyme complex consisting of two proteins: one is a
cytochrome P450 enzyme containing haem(CYP19) and the other is a reductase enzyme using
NADPH as cofactor. Aromatase catalysesthe last stage in the biosynthesis of estrogens from
androgens where an aromatic ring is formed.
Aminoglutethimidea reversible, competitive inhibitor, but has disadvantages in that it binds to various cytochrome
P450 enzymes and inhibits a range of steroid hydroxylations. This results in undesirable side effects.
Anastrozoleand letrozoleare more selective; The N-4 nitrogen of the triazolering interacts with the haemiron of
aromatase and prevents binding of the steroid substrate. The anilinonitrogen of aminoglutethimideserves the
same purpose.
Formestaneacts as a suicide substrate that permanently inactivates aromatase and is more selective in its action
than aminoglutethimide.

48. Hormone therapy
Aromatase inhibitors
Reactions catalyzed by aromatase
Reversible competitive aromatase inhibitors