ANTINEOPLASTIC AGENTS_250923_132027..pdf

Medicinal chemistry of antineoplastic agents

1. MEDICINAL CHEMISTRY OF
ANTINEOPLASTIC AGENTS

2. INTRODUCTION
•Cancer:groupofdiseasescharacterizedbyuncontrolledgrowthand
spreadofabnormalcellsthatleftuntreatedmayleadtodeath.
•Neoplasia:uncontrolledgrowthofnewtissuetheproductofwhichis
knownastumor&thesetumorsmaybeeithermalignantorbenign.
•Malignanttumorshavethecapabilityofinvadingsurroundingtissues
andmovingtodistantlocationinthebodyinprocesscalled
metastasisthatcharacteristicbenigntumorsdoesnotposses.

3. INTRODUCTION
•Canceroccursafternormalcellshavebeentransformedinto
neoplasticcellsthroughalterationoftheirgeneticmaterialandthe
abnormalexpressionofcertaingenes.
•Neoplasticcellsusuallyexhibitchromosomalabnormalitiesandthe
lossoftheirdifferentiatedproperties.Thesechangesleadto
uncontrolledcelldivisionandmanyresultintheinvasionofpreviously
unaffectedorgans,aprocesscalledmetastasis

4. Advances in Cancer Chemotherapy
•Surgery:
•Radiotherapy:
•Chemotherapy:killcells(ABs&anticanceragents)
•Hormones
•Immunotherapy and Gene therapy

5. Limitations of Therapy
•Cancercellsveryrapidlydevelopresistancetoantineoplasticdrugs.
•Differencesbetweennormalandneoplastichumancellsaremerely
quantitative.
•Biochemicalandmorphologicaldifferencesbetweennormaland
neoplasticcellsareslight;therefore,antineoplasticagentsaredevoidof
selectivetoxicitytotumorcells.
•Antineoplasticagentskillcellsbyfirst-orderkinetics,thatis,theykilla
constantfractionofcells.However,someofthecancercellseludekilling
andoneofthesecellsmayreestablishthetumor.Itisextremelydifficult
tokillallthemalignantcells.
•Mostantineoplasticdrugsarehighlytoxictothepatients.

6. CLASSES OF ANTICANCER AGENTS
•Generally divided into the following main classes:
a)Alkylating agents/ DNA crosslinking agents
b)Antimetabolites
c)Mitosis Inhibitors
d)Cytotoxic Antibiotics
e)Hormone therapy
f)Immunomodulators

7. 1. ALKYLATING AGENTS
A. Nitrogen mustards
•Bendamustine
•Chlorambucil
•Cyclophosphamide
•Ifosfamide
•Mechlorethamine
•Melphalan
•Thiotepa
B. Nitrosoureas
•Carmustine
•Lomustine
•Streptozocin
C. Organoplatinum
complexes
•Carboplatin
•Cisplatin
•Oxaliplatin
•Picoplatin
D. Procarbazine&
triazenes
•Dacarbazine
•Procarbazine
•Temozolomide
E. SULPHONIC ACID
ESTERS
•Busulphan
F. Ethyleneimines
•Triethylenemelamine
•Thiotepa& Tepa

8. ALKYLATING AGENTS
•AlkylationisdefinedasthereplacementofHonanatom(usually
nucleicacidsandproteins)byanalkylgroup.
Nu-H + alkyl-Y alkyl-Nu + H
+
+ Y
-
•Alkylatingagentsarehighlyelectrophiliccompoundsthatreactwith
nucleophilicgroups(particularly,butnotexclusively,theN-7of
guanine)onDNAtoformstrongcovalentbonds.
•Alkylationconvertsthebasetoaneffectiveleavinggroupsothat
attackbywaterleadstodepurinationandthelossofgenetic
informationiftheresultingdepurinationisnotrepairedbythecell.

9. Alkylation reaction

10. ALKYLATING 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.

11. NitrogenMustards
SARs
Aliphatic Rgroups
Push electrons to theN
E.g.Mechlorethamine
Morereactive
Too toxic for oraluse
Direct injection into the
tumor
Extravasation is a
common
Antidote is sodium
thiosulphate
Aromatic R groups
E.g.melphalan
Stabilize N byresonance
Reduce rate of
aziridinium ion
formation
Less reactive
Less toxic
Can be administeredorally
ALKYLATING AGENTS

12. ALKYLATING AGENTS: CYCLOPHOSPHAMIDE
•Cyclophosphamideisnotactiveuntilitistransformedbymetabolic
processtotheactiveformbyhepaticliverCytochromeP-450and
thus,itcouldbeclassifiedasabioprecursor.
•Themetabolic4-hydroxyderivativeisfirstformedandundergoesthe
followingmodifications:

13. Bioactivation of cyclophosphamide

14. ALKYLATING AGENTS: CYCLOPHOSPHAMIDE
•Theaziridiniumionistheprinciplecrosslinkingalkylatorformedfrom
cyclophosphamide.
•MaximumaziridiniumionformationoccursatpH7.4.
•Theacroleinformedfromthemetabolicdegradationof
cyclophosphamidecausesseverehemorrhagiccystitisleadingto
nephrotoxicityandurotoxicity.
•ThedrugMESNA(2-mercaptoethanesulfonatesodium)is
coadministeredwithcyclophosphamideandifosfamideasitis
conjugatedwithacroleinformingnontoxicmetabolite.

15. ALKYLATING AGENTS: CYCLOPHOSPHAMIDE
Cyclophosphamideisactiveorally&parenterally
againstchroniclymphocyticleukemia,myelomaand
acuteleukemiainchildren.

16. ALKYLATING AGENTS: IFOSFAMIDE
•Ifosfamideisananalogueofcyclophosphamide
thatisrelatedinstructure
•Ifosfamiderequiresmetabolicactivationby
CYP450.
•HydroxylationatC-4producesactiveunstable
carbinolamine metabolite, 4-
hydroxyifosfamide,whichdegradesfurtherto
formadditionalcytotoxicmetabolites.
•MESNAisalsouseasadjunctivetoprevent
hemorrhagiccystitis

17. 2. ANTIMETABOLITES
A. Antifolates
•Methotrexate
•Pemetrexed
•Pralatrexate
B. DNA methyltransferase
inhibitors
•Azacitidine
•Decitabine
•Nelarabine
C. DNA polymerase inhibitors
•Cladribine
•Cytarabine
•Fludarabine
•emcitabine
D. Pyrimidine antagonists
•Capecitabine
•Floxuridine
•Fluorouracil
E. Purine antagonists
•Mercaptopurine
•Thioguanine
F.Miscellaneous
antimetabolites
•Hydroxyurea
•Pentostatin

18. Antimetabolites
•AntimetabolitesstopthedenovosynthesisofDNAbyinhibitingthe
formationofthenucleotidesthatmakeuptheselife-sustaining
polymers.
•Therate-limitingenzymesofnucleotidebiosynthesisoftenarethe
primarytargetfortheantimetabolites,becauseinhibitionofthiskey
enzymeisthemostefficientwaytoshutdownanybiochemical
reactionsequence.
•Antimetabolitesalsoarecapableofinhibitingotherenzymesrequired
inthebiosynthesisofDNA,andmanycanarrestchainelongationby
promotingtheincorporationoffalsenucleotidesintothegrowing
DNAstrand.

19. Antimetabolites
•Theantimetabolitesserveasfalsesubstratesforcriticalnucleotide
biosynthesisenzymes.
•Theyenticetheenzymestochoosethemovertheendogenous
substrate,andoncetheydo,theantimetabolitesbindthem
irreversibly.
•Ifthebuildingblocknucleotidescannotbesynthesized,thenDNA
synthesis(andtumorgrowth)isstoppeddeadinitstracks.Iftumor
growthisarrested,thenmetastasisslows,andthepatienthasa
fightingchanceforremissionand/orcure.

20. Antimetabolites
Antimetabolite antineoplastics are categorized by the class of
nucleotide theyinhibit;
Purineantagonists
inhibit the synthesis of the purine-based nucleotides adenylate
monophosphate (AMP) and guanylatemonophosphate(GMP),
Pyrimidineantagonists
Stop the production of the pyrimidine-based nucleotides, primarily deoxythymidine
monophosphate(dTMP).
E.g folateantagonists

21. Pyrimidine Antagonists: Dihydrofolate
reductase inhibitors
•Dihydrofolatereductase(DHFR)is
anenzymewhichiscrucialin
maintaininglevelsoftheenzyme
cofactortetrahydrofolate(FH4).
•Withoutthiscofactor,thesynthesis
oftheDNAbuildingblock(dTMP)
wouldgrindtoahalt,which,inturn,
wouldslowdownDNAsynthesis
andcelldivision.
•Theenzymecatalysesthereduction
ofthevitaminfolicacidtoFH4in
twostepsviadihydrofolate(FH2).

22. Pyrimidine Antagonists: Inhibitors of
thymidylate synthase
•Methotrexatehasanindirecteffecton
thymidylatesynthasebyloweringthe
amountofN5,N10-methyleneFH4
cofactorrequired.
•5-Fluorouracilisananticancerdrugwhich
inhibitsthisenzymedirectly.
•5-Fluorouracilisconvertedinthebodyto
thefluorinatedanalogueof2′-
deoxyuridylicacidmonophosphate
(FdUMP)whichthencombineswiththe
enzymeandthecofactor.,thisterminates
DNAsynthesis.
•Capecitabineisaprodrugfor5-fluorouracil.

23. Purine Antagonists
•Thethiopurines6-mercaptopurine
and6-thioguanineareprodrugs
whichareconvertedtotheir
corresponding nucleoside
monophosphates bycellular
enzymes.
•Themonophosphatestheninhibit
purinesynthesisatanumberof
points.
•TheyarealsoincorporatedintoRNA
andDNA,leadingtocomplexeffects
whichendincelldeath.

24. Purine Antagonists: Inhibitors of
ribonucleotide reductase
•Ribonucleotidereductaseisresponsiblefortheconversionof
ribonucleotidediphosphatestodeoxyribonucleotidediphosphates
•Theenzymecontainsanironcofactorwhichiscrucialtothereaction
mechanism.
•Hydroxycarbamideisaclinicallyusefulagentwhichinhibitsthe
enzymebydestabilizingtheironcenter

25. Purine antagonists: Inhibitors of adenosine
deaminase
•Ribonucleotidereductaseisinhibiteddirectlybyhydroxycarbamide,
butitcanalsobeinhibitedindirectlybyincreasingthelevelofnatural
allostericinhibitorssuchasdATP.
•Theenzymeadenosinedeaminasecatalysesthedeaminationof
adenosinetoinosine
•Inhibitionoftheenzymeleadstoabuild-upofdATPinthecell,which,
inturn,inhibitsribonucleotidereductase.
•PentostatinisanaturalproductisolatedfromStreptomyces
antibioticus,andisapowerfulinhibitorofadenosinedeaminase.

26. Inhibitors of DNA polymerases
•DNApolymerasescatalysethesynthesis
of DNA usingthe four
deoxyribonucleotidebuildingblocks
dATP,dGTP,dCTP,anddTTP.
•Theanticancerdrugcytarabineisan
analogueof2′deoxycytidineandactsas
aprodrug.
•Itisphosphorylatedincellstothe
correspondingtriphosphatewhichacts
asasubstrateforDNApolymerasesand
becomeincorporatedintothegrowing
DNAchain.
•Thiscanleadtochainterminationor
preventreplicationofthemodifiedDNA.
•Gemcitabineisananalogueof
cytarabinewithfewersideeffects.

27. 3. MITOSIS INHIBITORS
•Cabazitaxel
•Docetaxel
•Estramustine
•Ixabepilone
•Paclitaxel
•Vinblastine
•Vincristine
•Vinorelbine

28. Mitosis inhibitors: Tubulin inhibitors
•Tubulinisastructuralproteinwhichiscrucial
tocelldivision.Theproteinactsasabuilding
blockformicrotubuleswhicharepolymerized
anddepolymerizedduringcelldivision.
•Drugscanblockthisprocessbyeitherbinding
totubulintopreventpolymerizationor
bindingtothemicrotubulestoprevent
depolymerization.
•Agentswhichinhibittubulinpolymerization:
Vincristine,vinblastine,vindesine,and
vinorelbinearealkaloidsderivedfrom
Catharanthusroseuscanbindtotubulinto
preventpolymerization.
•Podophyllotoxinformsacomplexwithtubulin
andpreventsthesynthesisofmicrotubules,
justlikecolchicine

29. Mitosis inhibitors: Tubulin inhibitors
Agents that inhibit tubulin depolymerization
•Paclitaxel(Taxol)andthesemi-syntheticanaloguedocetaxelare
importantanticanceragentsthatinhibittubulindepolymerization.
•Thebindingofpaclitaxelacceleratespolymerizationandstabilizesthe
resultantmicrotubules,whichmeansthatdepolymerizationis
inhibited.
•Asaresult,thecelldivisioncycleishalted.

30. Mitosis inhibitors: Topoisomerase Poisons
Epipodophyllotoxins e.getoposide and teniposide
•Theepipodophyllotoxinsaresemisyntheticglycosidicderivativesof
podophyllotoxin.
•Althoughthesecompoundsarecapableofbindingtotubulinandinhibiting
mitosis,theirprimarymechanismofantineoplasticactionispoisioning
topoisomeraseIIenzyme,justliketheanthracyclineantibiotics.
•Thedrugsshowselectivityforcancercells,despitethefactthattopoisomeraseII
ispresentinbothcancercellsandnormalcells

31. Mitosis inhibitors: Topoisomerase Poisons
Camptothecins e.gCamptothecin
•Camptothecinis a naturally occurring cytotoxic alkaloid which was
extracted from Camptothecaacuminate.
•It targets the complex between DNA and topoisomerase I

32. CYTOTOXIC ANTIBIOTICS
A. Anthracyclines and anthracenediones
B. Miscellaneous anticancer antibiotics

33. Antibiotics: Anthracyclines and
Anthracenediones
•ThereareseveralmechanismsbywhichtheseagentstargetDNA,
includingintercalation,alkylation,andstrandbreakageeitherdirectly
orasaresultofenzymeinhibition.
•Manyoftheantineoplasticantibioticcompoundsinhibit
topoisomeraseII,anenzymeresponsibleformaintainingproper
•DNAstructureduringreplicationandtranscriptiontoRNA.
•Yetanotherproposedmechanismofcytotoxicactionisthe
generationofcytotoxicfreeradicalsthatcausesingle-strandbreaks
inDNA

34. Antibiotics: Anthracyclines and
Anthracenediones
•Anthracyclineantineoplasticantibiotics
areverycloselyrelatedtothe
tetracyclineantibacterials.
•Structurally,theyareglycosidesand
containasugarportion(L-
daunosamine)andanonsugarorganic
portion.
•Thenonsugarportionofglycosidesis
genericallyreferredtoasanaglycone.
Inanthracyclines,theaglyconemoiety
isspecificallycalledanthracyclinoneor
anthroquinone.

35. Antibiotics: Dactinomycin
•Dactinomycinbindsnoncovalently
todouble-strandedDNAby
partialintercalationbetween
adjacentguaninecytosinebases
resultingininhibitionofDNA
function.
•Thestructuralfeatureof
dactinomycinimportantforits
mechanismofcytotoxicityisthe
planarphenoxazonering,which
facilitatesintercalationbetween
DNAbasepairs.

36. Antibiotic: Bleomycin
•Complex natural products
isolated from Streptomyces
verticillus
•MOA: The bithiazolering
system which intercalates
with DNA.

37. Hormone therapy
•Corticosteroids, estrogens, progestins, androgens
•Luteinizing hormone releasing hormone agents
•Antiestrogens
•Antiandrogens
•Aromatase inhibitors

38. Hormone therapy
•Hormone-basedtherapiesareusedforcancerswhicharehormone
dependent.
•Ifthecancercellrequiresaspecifichormone,thenahormonecan
beadministeredwhichhasanopposingeffect.
•Alternatively,hormoneantagonistscanbeusedtoblocktheaction
oftherequiredhormone.

39. Glucocorticoids, estrogens, progestins, and
androgens
•Glucocorticoidsincludeprednisoloneandprednisone.Prednisoneactsasaprodrugand
isconvertedenzymaticallytoprednisoloneinthebody.
•Estrogensinhibittheproductionofluteinizinghormone(Lh)and,bydoingso,
decreasethesynthesisoftestosterone.
•Themostcommonlyusedagentsareethinylestradiolanddiethylstilbestrol.Fosfestrolis
thediphosphateprodrugofdiethylstilbestrol.
•Progestinsusedasanticanceragentsincludemedroxyprogesteroneacetateand
megestrolacetate.
•AndrogensarethoughttosuppressproductionofLh,resultinginadecreaseinestrogen
synthesis;theseincludefluoxymesteroneandtestosteronepropionate(prodrugwhich
isconvertedtodihydrotestosterone)

41. Luteinizing hormone-releasing hormone
agonists
•Luteinizinghormone-releasinghormone(LHRH)isadecapeptidehormonewhich
bindstoreceptorsonanteriorpituitarycellsandstimulatesthereleaseofLH.
•Onlong-termexposuretolhrh,thereceptorbecomesdesensitizedleadingtoa
dropinlhlevels.SinceLHstimulatesthesynthesisoftestosterone,thisresultsin
loweredtestosteronelevels.
•Leuprolideandgoserelin,arebothdecapeptideanaloguesoflhrhdesignedtobe
moreresistanttopeptidasedegradation.

42. Hormonetherapy
Anti-estrogens
Tamoxifenandraloxifeneare
syntheticagentswhich
antagonize estrogen
receptorsandprevent
estradiolfrombinding.

43. Hormonetherapy
Anti-androgens
Flutamideandcyproteroneacetateareusedtotreatprostatecancerandworkby
blockingtheactionofandrogensattheirreceptors.
Abirateroneisapotentandselectiveinhibitorof17α-hydroxylase-17(20)-lyase,a
cytochromeP450enzymewhichisinvolvedinthebiosynthesisofandrogens

44. Hormonetherapy
Aromataseinhibitors
Aromatasecatalysesthelaststageinthebiosynthesisofestrogensfromandrogens
whereanaromaticringisformed.
Aminoglutethimideareversible,competitiveinhibitor,buthasdisadvantagesinthatitbinds
tovariouscytochromeP450enzymesandinhibitsarangeofsteroidhydroxylations.This
resultsinundesirablesideeffects.
Anastrozoleandletrozolearemoreselective;TheN-4nitrogenofthetriazoleringinteracts
withthehaemironofaromataseandpreventsbindingofthesteroidsubstrate.
Formestaneactsasasuicidesubstratethatpermanentlyinactivatesaromataseandismore
selectiveinitsactionthanaminoglutethimide.

45. Hormonetherapy
Aromatase
inhibitors
Reactions catalyzed by
aromatase
Reversible competitive aromatase
inhibitors