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Chapter13AntineoplasticAgentsMalignanttumorisaseriousthreattohumanhealthandthefrequently-occurringdiseases,thehumandeathcausedbymalignanttumorsisthesecondplaceamongthedeathofalldisease.Therapy：SurgicaloperationRadiationtherapyChemicaltreatmentAntineoplasticagentsaimatanti-malignanttumor,alsoknownasanti-cancerdrugs.Classificationbymechanism•1.Alkylatingagents•2.Antimetabolites•3.Drugsinteferingwithsynthesisofproteinoftumorcells13.1Biologicalalkylatingagents•1.Nitrogenmustards•2.Ethyleneimines•3.Sulfonatesandhalogenatedpolyols•4.Nitrosourea•Bioalkylatingagentsarecytotoxicdrugs.Invivo,itisabletoformapositivechargedcarbon-ionorotheractiveelectrophilicgroups,andthentheelectrophilicionscombinecovalentlywithelectronrichgroups(suchasamino,sulfhydryl,hydroxyl,carboxyl,phosphate,etc.)ofthecellsofbiologicalmacromolecules(DNA,RNA,enzymes),leadtothebreakingofDNAmolecule,atlastresultinthedeathoftumor.•However,bioalkylatingdrugsalsoinhibitthenormalcellswiththepropertyofrapidproliferationsuchasbonemarrowcells,intestinalepithelialcellsatsametime.Sothebioalkylatingagentshavemoreserioussideeffects,suchasnausea,vomiting,bonemarrowsuppressionandhairloss.Clinicalusuallyarecarryingoncombinedusewithotherdrugs.BiologicalalkylatingagentsGeneralformulaofnitrogenmustardsNCH2CH2ClCH2CH2ClR载体部分烷基化部分（1）Fractionofalkylationisanti-tumorfunctiongroup,existingasbis-β-chloro-ethylamine.（2）Fractionofcarrier：可以改善药物药代动力学性质，选用不同载体，可提高选择性和抗肿瘤活性。依据载体化学结构，可分为脂肪氮芥、芳香氮芥、氨基酸氮芥、杂环氮芥和甾体氮芥。13.1.1NitrogenmustardsMechlorethaminehydrochlorideN-甲基-N-（2-氯乙基）-2-氯乙胺盐酸盐N-methyl-N-(2-chloroethyl)-2-chloroethylaminehydrochlorideClinicalapplication:mainlytreatmentforlymphosarcomaandHodgkin'sdiseaseDevelopment:duringtheFirstWorldWar,nitrogenmustardwasusedasatoxicgas,shortlyafteritwasfoundthepropertyofinhibitingbonemarrowandlymphoidtissueofthevictims.In1942,GilmanfromYaleUniversityfirstlyusednitrogenmustardinthetreatmentoflymphoidneoplasms.NCH3ClClHClNRClClSClCl芥子气烷基化部分载体部分DifferentR：脂肪氮芥、芳香氮芥Alkylationprocess:NRClCl-ClNRClXNRClX-ClNRXYNRYX乙撑亚胺离子脂肪氮芥的氮原子碱性比较强，烷基化历程是双分子亲核取代反应，活泼的乙撑亚胺离子极易与细胞成分的亲核中心起烷化作用，属强烷化剂。Itisusuallyusedasinjectiondrugofaqueoussolution,whichpHvaluemaintainedat3.0~5.0.Stability：NCH3ClClH2OpH7NCH3OHOHChlormethinehydrochloridepresentedstrongdestructiontotumorcells,butwithpoorselectivityandlargetoxicity.OnlyEffectiveforlymphoma,sostructuralmodificationisnecessary.Nitromin:Reducedthepossibilityofformationofethyleneimineforthereducedelectroniccloudonnitrogen.Nitrominislesstoxicity,butalsothereducedanti-tumoractivity.NCH3ClClO2.Aromaticnitrogenmustards:Theintroductionofaromaticringledtoreductionofalkalescencebyreasonofconjugation,somechanismwaschanged,noformationofcyclicethyleneimineionbuttheformationofcarboncationintermediate.NArClCl-ClX-ClYNArClNArClXNArXNArYXHOOHOOCHNHRR=HR=CHO溶肉瘤素氮甲苯丁酸氮芥NClClNClClCyclophosphamide123456P-[N，N-双-（β-氯乙基）]-1-氧-3-氮-2-磷杂环己烷-P-氧化物一水合物。Withabroadspectrumofanti-tumor。Physicochemicalpropertiesofcyclophosphamide•Whitecrystalorcrystallinepowder(失去结晶水即液化)•Soluableinwater,unstableinaqueoussolutionandeasilyhydrolyze,easilydecomposeunderheatingcondition.•Cyclophosphamideisaprodrug.在肝脏被活化，经非酶促的β-消除反应生成丙烯醛（膀胱毒性）、磷酰氮芥及去甲氮芥，三者都是较强的烷化剂。POHNNO肝脏酶正常组织酶正常组织肿瘤细胞4-羟基环磷酰胺磷酰氮芥(ClCH2CH2)2POHNNO(ClCH2CH2)2OHPONH2NO(ClCH2CH2)2CHOPOHNNO(ClCH2CH2)2OPONH2NO(ClCH2CH2)2COOHPONH2NO(ClCH2CH2)2+CH2CHCHOHNClClCyclophosphamidehasabroadspectrumofanti-tumor,clinicalfortreatmentofmalignantlymphoma,acutelymphocyticleukemia,multiplemyeloma,lungcanceretc.ClinicalapplicationofcyclophosphamideNHHOCH2CH2HOCH2CH2NClCH2CH2ClCH2CH2CH2HOCH2NH2CH2PClClOHNPOONClCH2CH2ClCH2CH2HNPOONClCH2CH2ClCH2CH2H2O．POCl3C5H5NClCH2CH2ClH2OCH3COCH3以二乙醇胺作为原料，用过量的三氯氧磷同时进行氯代和磷酰化，制得氮芥磷酰二氯，再与3-氨基丙醇缩合。Synthesisofcyclophosphamide美法仑MelphalanNH2*CH2NCH2CH2ClCH2CH2ClCHCOOH氮芥类的烷化剂，结构包括氮芥和L-苯丙氨酸部分，氮芥部分在碱性水溶液中易水解，含有α－氨基酸结构，会发生茚三酮显色反应，且有氨基酸两性性质。•氮芥类药物是通过在体内转变成乙撑亚胺中间体发挥烷化剂作用，乙撑亚胺的磷酰胺衍生物，可提高抗肿瘤作用及减小毒性。•Tepawasclinicalusedfortreatmentofleukaemi。•Thiotepachangedintotepainvivo.Clinicalforthetreatmentofbreastcancer,ovariancancer,bladdercancer,andsoon.13.1.2EthyleneiminesTepaThiotepaSulfonatesandhalogenatedpolyolsarenon-nitrogenmustardalkylatingagents。甲磺酸酯是较好的离去基团，生成碳正离子与生物大分子发生亲核取代反应进行烷基化。Busulfan,alsoknownasMyleran,namedas:4-Butanedioldimethylsulfonate。Clinicalforthetreatmentofchronicmyeloidleukemia.多元醇类药物主要是卤代多元醇，进入体内后会形成双环氧化物而产生烷化作用。二溴甘露醇(Dibromomannitol)、二溴卫矛醇(Dibromodulcilol)等。13.1.3Sulfonatesandhalogenatedpolyols13.1.4NitrosoureasN-亚硝基的存在使该氮原子与邻近羰基之间的键变得不稳定，在体内分解生成亲电性基团，破坏DNA的结构。。Nitrosoureasarehighlylipophilic,easilypassthroughtheblood-brainbarrierfortreatmentofbraintumors,centralnervoussystemtumorsandmalignantlymphoma,butwithsideeffectsofdelayedbonemarrowsuppression.ClinicaluseddrugsincludesCarmustine（卡莫司汀），Lomostine(洛莫司汀)，Semustine(司莫司汀)，Nimustine(尼莫司汀)andsoon.卡莫司汀CarmustineClNHNOClNON，N’-双（β-氯乙基)-N-亚硝基脲，又名卡氮芥N,N'-bis-(β-chloroethyl)-N-nitrosoureaCarmustineishighlylipophilic,easilypassthroughtheblood-brainbarrierforthetreatmentofbraintumors,othercentralnervoussystemtumorsandmalignantlymphoma.NHOOHON