Anti-Cancer Drugs-Alkylating agents

Dr.Narmin Hamaamin Hussen

1. Anti-Cancer Drugs
(Part One)
Medicinal Chemistry IV / 2
nd
Semester / 4
th
Class
Lecture 3
Dr.Narmin Hamaamin Hussen
2021-2022
World Cancer Day on February 4
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2. Introduction
▪Cancerisnotasingledisease.Itisagroupofmorethan200
differentdiseases.
▪Cancermayspreadtootherpartsofthebody.
▪Currently1in4deathsinUSAareduetocancer.
▪Iraqicancerdatafor2020announcedthatthereareover33,837
cancerandtumor-relatedcases.
▪CancerisconsideredoneoftheleadingcausesofmortalityinIraq,
contributingtoanestimated11%oftotaldeaths.
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3. Erbil and Duhok governorates’ cancer incidence stratified by gender (2013 to 2019)
Reference:DOI:10.31557/APJCP.2022.23.2.601
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4. What is cancer?
▪Cancerischaracterizedbyanabnormalanduncontrolled,
divisionofcells,whichproducestumoursandinvadesadjacent
normaltissues.
▪Often,cancercellsseparatethemselvesfromtheprimary
tumour,andarecarriedbythelymphaticsystemtoreach
distantsitesoftheorgans,wheretheydivideandform
secondarytumours(metastasis).
▪Apoptosisistheprocessofprogrammedcelldeath.Itisused
duringearlydevelopmenttoeliminateunwantedcells.
Apoptosisalsoplaysaroleinpreventingcancer.
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5. Phases of the Cell Cycle
Regulation
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6. Types of Tumors
Notalltumorsarecancerous;tumorscanbebenignormalignant.
➢Benigntumorsaren'tcancerous.Theycanoftenberemoved,and,inmostcases,theydo
notcomeback.Cellsinbenigntumorsdonotspreadtootherpartsofthebody.
➢Malignanttumorsarecancerous.Cellsinthesetumorscaninvadenearbytissuesand
spreadtootherpartsofthebody.Thespreadofcancerfromonepartofthebodyto
anotheriscalledmetastasis
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7. Stages of cancer
▪Cancerstagingistheprocessofdeterminingtheextent
towhichacancerhasdevelopedbygrowingand
spreading.
▪Thereareseveralmethodsofstagingincludingthe
commonlyusedTNMsystem,whereT—tumor,N—
lymphnodeinvolvement,andM—metastasis.Inthis
system,TandNarefollowedbynumbers(1,2,3,etc.)
toindicatethesizeofthetumorandtheextentof
lymphnodeinvolvement,respectively,wherehigher
numbersareassociatedwithmoreadvanceddisease.
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8. Causes and Risk factors
1.Environment
▪cigarettesmoke
▪chemicals
▪UVlight
▪viruses
2.Metabolicprocesses
▪freeradicals
▪DNAcopyingandrepairdefects
3.Inheritedgeneticmutations
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9. Cancer therapeutics modalities(classical)
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10. The Classification of Anticancer Drugs According to chemical structure and
resource of the drug
1.Alkylating agents
2.Antimetabolites
3.Antibiotics
4.Plant products
5.Enzymes
6.Hormones
7.Immuno therapy
8.Monoclonal antibodies
9.Radio-therapeutic agents
10.Cyto-protective agents: Mesna, Amifostine, Dexrazoxane
11.Miscellaneous
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11. Cell cycle specificity of Anti-Neoplastic agents
▪Drugs that act during a specific phase of the cell
cycle
The Classification of Anticancer Drugs According to the cycle or phase
specificity of the drug
Cell cycle Non-specific agents
▪CellCycleNonspecificAgents(CCNSA)drugs
thatareactivethroughoutthecellcycle
➢AlkylatingAgents
➢PlatinumCompounds
➢Antibiotics
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12. I. Alkylating agents
a.Nitrogenmustards:Mechlorethamine,IfosamideCyclophosphamide,Melphalan,Chlorambucil
b.AlkylSulphonate:Busulfan
c.Nitrosoureas:Carmustine,Lomustine,Semustine,Chlorozotocin
d.Aziridines:Thiotepa,Altretamine
e.Methylhydrazines:Procarbazine
f.Imidazolecarboxamide:Dacarbazine,Temozolomide
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13. ▪Thealkylatingagentsareaclassofdrugsthatarecapableofintroducinganalkylgroupintonucleophilic
sitesonDNA,RNAoranyenzymethroughcovalentbond.
▪Thesecompoundsproducehighlyreactivecarboniumionintermediatesthattransferalkylgrouptocellular
macromoleculesbyformingcovalentbond.
▪Theseagentsarethoughttoreactwiththen7positionofguanine(oranyothernitrogenbase)ineachof
thedoublestrandsofDNA,causingcross-linkingthatinterfereswithseparationofthestrandsandprevents
mitosis.BlocksDNAsynthesis
▪AlkylationofDNAisthoughttoleadtocelldeath,althoughtheexactmechanismisuncertain.Potential
mechanismsofcelldeathincludeactivationofapoptosiscausedbyp53activationanddisruptionofthe
templatefunctionofDNA.
Alkylating agents
Mechanism of action:
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14. alkylating agents
Alkylation of guanine N-7 and subsequent depurination of DNA. 14

15. A-Nitrogen mustards
▪Nitrogenmustardsgettheirnamebecausetheyarerelatedtothesulfur-containingmustardgasesusedduring
FirstworldWar.Theterm“mustard”comesfromthesimilarityintheblistersproducedbythecompoundand
thoseseenuponexposuretotheoilofblackmustardseeds.
▪Nitrogenmustardscontainbis(2-chloroethyl)group,modificationofthisgroupchangestability,reactivityand
lipophilicity.
➢Mechlorethamine(2-chloro-n-(2-chloroethyl)-n-methylethanamine)
▪Ishighlyreactive,infact,tooreactiveandthereforenonselective,makingitunsuitablefororaladministrationis
takenonlybyivinfusion(isavailablein10-mgvials,directinjectionintothetumor)anditusedtotreat
Hodgkin’slymphomaandnon-Hodgkin’slymphoma
▪Amajordisadvantageofmechlorethamineisthatithasmutagenicandcarcinogeniceffectonbonemarrow
stemcells(hemodynamicchange),nausea,vomitingandskintoxicity.
CH3 . HCl
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16. ▪Mustardssuchasmechlorethamineareclassifiedasdialkylatingagentsinthatonemustardmoleculecan
alkylatetwonucleophiles.
▪Theinitialacid–basereactionisnecessarytoreleasethelonepairofelectronsonnitrogen,which
subsequentlydisplaceschloridetogivethehighlyreactiveaziridiniumcation.
▪Nucleophilicattackcanthenoccurattheaziridiniumcarbontorelievethesmallringstrainandneutralize
thechargeonnitrogen.Thisprocesscanthenberepeatedprovidedasecondleavinggroupispresent
Alkylation of nucleophilic species by nitrogen mustards.
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17. 17

18. ▪Skintoxicityduetonitrogenmustardextravasationis
severeandtypicallyprolongedoverseveralmonths.
▪Sodiumthiosulfateisbelievedtochemicallyneutralize
reactivemechlorethamine-alkylatingspeciesandthus
decreaseskintoxicity.
▪MechanismofactionNeutralizesmechlorethamineto
formnontoxicthioestersthatareexcretedintheurine.
▪Incasesofextravasation(drugescapesfromthe
intravenousveinintothesurroundingtissue,thiscan
causelocalpainaccompaniedbyburningorstinging,
blistering,erythema,swelling,andtenderness.),the
antidotesodiumthiosulfate(Na2S2O3),astrong
nucleophile,maybeadministered.Itiscapableof
reactingwithelectrophilicsitesonthemustard,and
oncereactionhasoccurred,theresultingadducthas
increasedwatersolubilityandmaybereadilyeliminated.
▪Cancerpatientsareatanincreasedriskofextravasation
becauseofthefragilityoftheirveinsresultingfrom
radiation,previouschemotherapytreatments,or
malnutrition
Antidote of Mechlorethamine
Thiosulfate inactivation of mechlorethamine
✓Inject2mlofthesodiumthiosulfatesolutionforeach
milligramofmechlorethaminesuspectedtohave
extravasated.Injectthesolutionsubcutaneouslyinto
theextravasationsiteusinga25-gaugeorsmaller
needle(changeneedlewitheachinjection).
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19. ➢ChlorambucilandMelphalan
▪Thelackofselectivityofmechlorethamineledtoattemptstoimproveontheagent.Onerationalewasto
reducethereactivitybyreducingthenucleophilicityofnitrogen,therebyslowingaziridiniumcation
formation.Thiscouldbeaccomplishedbyreplacementoftheweaklyelectron-donatingmethylgroupwith
groupsthatwereelectronwithdrawing
▪Thisisseeninthecaseofchlorambucilandmelphalanbyattachmentofnitrogentoaphenylring
➢Chlorambucil
▪Veryslowacting
▪Highlyselectiveonlymphoidtissue,verylittleeffectonmyeloidtissue
▪Usedinchroniclymphocyticleukemia(CLL)andnon-Hodgkin’slymphoma
▪Suitableonlyfororaladministration
➢Melphalan
▪Usedinmultiplemyeloma,OvariancancerandMalignantmelanoma
▪SuitablefororaladministrationandIvinfusion
melanoma
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20. ➢Cyclophosphamide:
▪Cyclophosphamideisavailablein25-and50-mgtabletsfororaladministrationand100-,200-,500-,1,000-,
and2,000-mgvialsforIVuse
▪Usedinthetreatmentofawidevarietyofcancers,includingbreastcancer,nonHodgkin’slymphoma,chronic
lymphocyticleukemia,ovariancancer,boneandsofttissuesarcoma.
▪Alsoithasapotentimmunosuppressantproperty
▪Thismostwidelyusedalkylatingagent,itisinactive(Prodrug)invitrobutwhenitadministereditis
metabolizedbyliverintophosphoramidemustard(activecompound).
▪Inthecaseofcyclophosphamide,itwasinitiallybelievedthatthedrugcouldbeselectivelyactivatedin
cancercellsbecausetheywerebelievedtocontainhighlevelsofphosphoramidaseenzymes.Thiswould
removetheelectron-withdrawingphosphorylfunctionandallowaziridineformationtooccur.
▪dehydrogenase
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21. Metabolic and chemical activation of cyclophosphamide
Toxic metabolite
Active
Inactive
In Liver
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22. Molecular Mechanisms of Acrolein Toxicity
▪Acrolein-inducedoxidativestressisassociatedwithseveretoxicityintherenalsystemdueto
theuseofanticanceragentssuchascyclophosphamideandifosfamidethatgetmetabolizedto
acrolein
DetoxificationofAcrolein:
▪MESNEX(Mesna)isadetoxifyingagenttoinhibitthehemorrhagiccystitisinducedby
cyclophosphamideorifosfamide.Theactiveingredient,Mesna,isasyntheticsulfhydryl
compounddesignatedassodium-2-mercaptoethanesulfonate
▪AcroleintoxicityispreventedbyMesnawhichbindswithandclearsacrolein.
▪MESNEXinjectionisgivenasintravenousbolusinjectionsinadosageequalto20%ofthe
ifosfamideorcyclophosphamidedosage(w/w)atthetimeofifosfamideorcyclophosphamide
administration.
▪TherecommendeddoseoforalMesnais40%ofthecyclophosphamideorifosfamidedose,
givenpriortoantineoplasticagentsandthenrepeatedat2hoursand6hoursafterthe
cyclophosphamide/ifosfamidedose
Adverse Effect of Cyclophosphamide (CP)
1-Hemorrhagic cystitis( inflammation urinary bladder) . A metabolite of CP, acrolein, is largely
responsible
2-Alopecia
Cyclophosphamide
Or Cyclophosphamide
Mesna
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23. CoadministrationofMesnaisrecommendedwithCyclophosphamide
Detoxification of cyclophosphamide by Mesna
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24. ➢Ifosfamide (Iphosphamide, IFEX):
▪Ifosfamideisavailablein1-and3-gvialsforIVadministrationasFoodandDrugAdministration(FDA)-
approvedthird-linetherapyinthetreatmentoftesticularcancer.
▪AlsobeenutilizedinthetreatmentofawidevarietyofcancersincludingHodgkin’sandnon-Hodgkin’s
lymphoma,softtissuesarcoma,germcelltumors,smallcelllungcancer,non–smallcelllungcancer
(NSCLC),cancersoftheheadandneck,bladdercancerandcervicalcancer.
▪Asyntheticanalogofcyclophosphamide
Adverseeffect:Hemorrhagiccystitis
▪Coadministrationofmesnaisrecommended.
▪Incontrasttocyclophosphamide,thereisagreateramountofdeactivationoftheagentbyN-
dechloroethylationandsubsequentlymorechloroacetaldehydeisproduced,whichmayresultinagreater
amountofneurotoxicityandnephrotoxicitythanseenwithcyclophosphamide.
▪Neurotoxicity,whichisassociatedwiththeproductionofchloroacetaldehydepresentsasconfusion,
seizure,weakness,andhallucination,andcomamayoccur.
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25. Metabolic and chemical activation of ifosfamide.
Toxic
Toxic
Toxic
Active
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26. B-Alkyl Sulphonate
➢Busulfan
▪Busulfanisavailableas2-mgtabletsfororaladministrationand10-mLforIV
administration
▪Highlyselectiveformyeloidelements(forgranulocytesprecursorsthan
plateletsandredbloodcell)
▪Usedinthetreatmentofchronicmyelogenousleukemia(CML,atypeof
cancerofthewhitebloodcells)andinhigh-dosetherapyforrefractory
leukemiawithbonemarrowtransplant.
▪Busulfanisabifunctionalalkylan,asulfonicacidalkylester,.
▪Busulfanutilizestwosulfonatefunctionalitiesasleavinggroupsseparatedby
afour-carbonchainthatreactswithDNAtoprimarilyformintrastrandcross-
linkat5-GA-3sequences
▪Theagentiswellabsorbedwhengivenorally,welldistributedintotissues,
andcrossestheblood-brainbarrier.
Adverseeffect:
▪Skinpigmentation
▪Pulmonaryfibrosis
▪Hyperuricemia
CML
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27. Structure of busulfan (alkyl alcanesulfonates) and of its mechanism of DNA or protein alkylation
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28. C-Nitrosoureas
➢Carmustine
▪Ithashighlipidsoluble
▪Itpossessesthepotentialtocrosstheblood-brain-barrier,carmustineisemployedspecificallyforbraintumoursandother
tumours,forinstanceleukemias,whichhavemetastasizedtothebrain.Acombinationofcarmustineandprednisoneis
usedforthetreatmentofmultiplemyeloma.Asasecondarytherapyitisfrequentlyemployedinconjunctionwithother
antineoplasticagentsforlymphomasandHodgkin’sdisease.
▪The‘drug’mostprobablyexertsitsactionduetotheabilitytocross-likecellularDNA.ThustheverysynthesisofbothDNA
andRNAisinhibited.Itisspecificallyphasenonspecific.
➢Lomustine
▪Itisemployedeffectivelyinthetreatmentofprimaryandmetastaticbraintumours.Itisalsousedassecondarytherapyin
Hodgkin’sdisease.
▪Justlikecarmustine,itaccomplishesmaximumconcentrationsintheCSFchoicestatusforthetreatmentofglioblastoma
Carmustine
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29. ▪Theirmechanismofactionreliesontheformationofdiazohydroxyde
inbasicconditions,thatinturngeneratesareactivecationresponsible
foralkylationwhichtakesplaceprimarilyonO6orN7positionsof
guanines
▪O6Galkylationbycarmustineisdescribed
▪First,achloroethylatedadductisgeneratedandisfollowedbythe
formationofaN1G:N3Cinter-strandcross-link
▪Thistypeoflesioncontributestothecytotoxicityofnitrosoureastothe
sameextentthanothercross-linkssuchasO6G:N1CorN7G:N3C.
▪Proteincarbamoylationonlysineorarginineresiduesinducedby
isocyanatecouldalsoimpairtheactivityofkeyproteinsinvolvedincell
survivalsuchasDNArepairfactors.
Adverseeffect:
▪Nauseaandvomiting
▪Bonemarrowsuppression
▪Visceralfibrosis
▪Renaldamage
carmustine
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30. D-Ethylenimine or Aziridine:
➢Thiotepa (triethylenethiophosphoramide):
▪Inactivedrug(prodrug),
▪Thiotepaisavailablein15-mgvialsforIVadministration.
▪Usedinthetreatmentofbladdercancer,ovariancancer,andbreastcancer.
▪Hightoxicity
▪The‘drug’alsocrossestheblood-brainbarrier(BBB)(neurotoxicity)
▪Thiotepa,ahighlylipophilic,alkylatingagent,and/oritsactivemetabolitesmaybeexcretedinpartviaskininpatients
receivinghigh-dosetherapy(cutaneoustoxicityinpediatric)
▪MetabolismmediatedbyCYP2B1andCYP2C11effectsdesulfurizationtogiveanactivecytotoxicmetaboliteknownas
Triethylenephosphoramide(TEPA)fromwhichaziridinemayarise.Aziridinemetabolismoccurs,withliberationof
ethanolamine.
Metabolic and chemical interactions of thiotepa with DNA
Active
cutaneous toxicity
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31. ➢Altretamine
▪Altretamineisavailablein50-mgcapsulesfororaladministrationasasecond-linetreatmentfor
ovariancancer.
▪Themechanismofactionhasnotbeenfirmlyestablished,althoughthespectrumofactivityis
similartothatforotheralkylatingagents;however,cross-resistanceisnotseen.
▪Cytotoxicityhasbeencorrelatedwithmetabolismtogivethecarbinolamines,whichmayform
iminescapableofcrosslinking,ordecomposetogiveformaldehyde,whichmayreactwith
nucleophilesonDNAorproteins.
▪Theagentiswellabsorbeduponoraladministration,welldistributed,andhighly(90%)plasma
proteinbound.TheagentisextensivelymetabolizedintheliverbyCYPtogivedemethylated
metaboliteviathepreviouslymentionedcarbinolamines
Altretamine
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32. E-Methylhydrazines
➢Procarbazine hydrochloride (PCZ):
▪Procarbazineisavailablein50-mgtabletsfororaladministrationinthetreatmentofHodgkin’sandbraincancer.
▪ThemajormechanismsofresistanceappeartobeenhancedactivityofDNA-repairenzymesincludingenhancedO-6-
alkylguanineDNAtransferase(AGAT)whichremovesthemethylgroupfromtheO-6ofguanine.
▪Chromosomaldamageandalsoinhibitersofnucleicacidsynthesis
▪Theagentisrapidlyandcompletelyabsorbedafteroraladministrationandextensivelymetabolizedinthelivertogive
azoprocarbazinefollowedbyfurtheroxidationtomethyldiazineandthealdehyde.Theparentdrugandmetabolitescross
theblood-brainbarrier.
▪Eliminationoccursintheurinemostlyasmetaboliteswithaneliminationhalf-lifeof1hour.
Adverseeffect:
▪Myelosuppressionisdoselimiting,generallypresentingasthrombocytopeniathatmaybefollowedbyleucopenia.Glucose-
6-phosphatedehydrogenasedeficientpatientsmaydevelophemolyticanemiaduringprocarbazinetherapy.
▪weakMAOinhibitors
▪Sedation(passBBB)
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33. Metabolic and chemical activation of procarbazine
Alkylation mainly takes place on O6 position of guanines
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34. ➢Dacarbazine (DTIC) and Temozolomide
▪Dacarbazinealsoknownasimidazolecarboxamide,isachemotherapy
medicationusedinthetreatmentofmelanomaandHodgkin's
lymphoma.ForHodgkin'sitisoftenusedtogetherwithvinblastine,
bleomycin,anddoxorubicin.Itisgivenbyinjectionintoavein.
▪Temozolomideisanimidazotetrazinederivativeofthealkylatingagent
dacarbazine.
▪Temozolomideisnotactivebutundergoesrapidnonenzymatic
conversionatphysiologicpHtothereactivecompoundmonomethyl5-
triazinoimidazolecarboxamide(MTIC),whichisalsotheactivemethyl
group–donatingmetaboliteofDTIC.
▪Incontrast,MTICisformedfromdacarbazineonlyaftermetabolismby
theliver.Becausehepaticmetabolismcanbeinfluencedbyagents
commonlytakenbybrain-tumorpatientssuchasanticonvulsant
drugsandcorticosteroids,itisthoughtthatbioavailabilityofMTICmay
bemoreconsistentwithtemozolomidethanwithdacarbazine.In
addition,temozolomideisadministeredorallyandhasstrongcapacityto
enterthecerebrospinalfluidwithoutaccumulationwithrepeatdosing,
furthercontributingtoitsrapidlydevelopingclinicalinterestand
applications
O6 position of guanines
Temozolomideisused
totreatspecifictypes
ofbraincancer(eg,
glioblastoma
multiforme,anaplastic
astrocytoma)
F-Imidazole carboxamide
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35. ✓What is the role of the p53 gene in cancer?
✓What is the difference reaction mechanism between a carbonium
ions and carbanion?
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36. 36