烷基化试剂课件

CancerTherapyThespecificapproachusedtotreatcancerdependsuponthespecifictype,location,andstageofthecancerFundamentaltechniquesavailabletotreatcancer:SurgeryRadiationtherapyImmunologictreatmentChemicalbasedapproachesGenerally,eachhasitsownmerits,andacombinationofthesemethodsisusedSurgery:ThecancermuststillbeintheprimarytumorstageAhighdegreeofconfidencethattheentiretumorcanbeexcisedRemovingthetumorwithoutcausingsignificantdamagetovitalorgansRadiationtherapy:isusedtoshrinkordestroytumorsThisapproachrequiresthatthetumorbelocalizedX-rayradiationisusedbyfocusinganX-raybeamonthetumorImmunologicTherapy:UtilizetheimmunesystemtoeradicatethecancerThismethodologyattemptstoboostthelevelofT-cellandB-cellThemajorroleofT-cellistodestroyforeigncells,includingmalignantcellsB-cellisproducedinthebonemarrowandlymphnodes,makeantibodiesinresponsetoaforeignproteinSection2CancerChemotherapy一AlkylatingAgents（烷基化试剂）1Nitrogenmustards（氮芥）mechlorethamineMechanismofAction氮丙啶鎓AlkylationofguanineinDNAbyanalkylatingagentOncealkylationoccurs,thealkylatedsitesbecomepronetocleavage

鸟嘌呤2.Melphalan（美法伦）L-L-PhenylalaninemustardorL-PAML-PAMcanbepreferentiallytransportedintocells,withtheassistanceofL-aminoacidactivetransporter3.Cyclophosphamide（环磷酰胺）

Reducednucleophilicitybecauseoftheamide-likephosphoramidelinkageLesslikelytoformanaziridiniumionChemicallymorestableRequiresmetabolicactivation(pro-drug)SynthesisofCyclophosphamide（环磷酰胺的合成）AcidichydrolysisofcyclophosphamidepH4.0-6.0（环磷酰胺的酸性水解）氮芥磷酰二氯3-氨基丙醇OtherAlkylatingAgentsAziridineDerivativesLessreactiveagentsAziridineisathree-memberednitrogenheterocyclethatreactswithnucleophilesinordertorelieveringstain氮丙啶为三元杂环，和亲核试剂或基团反应开环，可释放环的张力三乙蜜胺替哌塞替哌氮丙啶衍生物，乙撑亚胺类提高抗肿瘤作用减少毒副作用白血病前药P450作用下转化为替哌乳腺癌最早用于临床安徽阜阳大头娃Thiotepa（塞替哌）anditsmetabolicproductTEPA（替哌）塞替哌pKa=6.0OtherAlkylatingAgentsQuinoneastransporterQuinonepartcanreducetheelectrondensity,decreasedtoxicity醌部分可降低电子云密度，降低药物的毒性QuinonepartcaninterfereenzymaticRe-Ox,inhibittumorcelldivision醌类化合物干扰酶系统氧化-还原过程，抑制肿瘤细胞的有丝分裂癌抑散三亚胺醌卡波醌Metabolicactivationofquinoneaziridine还原单氢醌氢醌ActivationoftheaziridinepartOtherAlkylatingAgents-MitomycinC（丝裂霉素C）Quinonemoiety,theaziridinering,thecarbamatePoororalabsorption,administeredIVTreatpancreaticcancer,胰腺癌antibioticBio-reductiveactivationofmytomycinCandDNAalkylationStabilityofMitomycinC（三）Methylsulfonate（甲磺酸酯类）

Busulfan，

白消安，马利兰CH3SO3isaverygoodleavinggroup（甲磺酸基是很好的离去基团）对白血病疗效显著（四）Nitrosoureas（亚硝基脲类）Carmustine，卡莫司汀

MechanismofActionReactivespeciesReactivespeciesReactivespeciesReactivespeciesFormationofavinylcationfromcarmustineTextbook,page544,图21-1广谱抗肿瘤活性，可通过BBBSynthesisofNirosoureas（亚硝基脲类）CarmustineOtherNitrosoureaanalogs洛莫司汀司莫司汀尼莫司汀（五）三氮烯咪唑类衍生物Dacarbazine（DTIC）达卡巴嗪Proposedmetabolismandmechanismofactionofdacarbazine5-Amino-4-carboxamide5-（3，3-dimethyl-1-triazenyl)-1H-imidazole-4-carboxamideDTIC主要用于治疗黑色素病、霍杰金氏病鸟嘌呤烷基化鸟嘌呤被DTIC（diazomethane）烷基化六：肼类，Procarbazine（丙卡巴肼）MetabolicactivationofprocarbazineProdrug偶氮甲基肼二、Cisplatin（顺铂）MechanismofActionofCisplatin与鸟嘌呤碱基N7配位形成五元环，扰乱DNA的正常双螺旋，使局部变性失活DNA的复制停止Note:onlythecis-isomerisactive三、Bleomycin,DactinomycinD,Homoharringtonine博来霉素、放线菌素D和高三尖杉酯碱Bleomycins:antitumorantibiotic，糖肽类discoveredin1966IsolatedfromStreptomycesverticillus放线菌Thetwosugarring:possiblecellrecognitionanduptakesiteTheimidazole,amideandtheamine:Iron2+(Fe2+)chelatingsiteThethiazolerings（二噻唑环）:DNAbindingsites主要用于治疗皮肤癌二噻唑糖咪唑嘧啶2、DactinomycinD,放线菌素DIsolatedfromStreptomycesparvullusThisringsystemisaromatic,planar,canintercalateorinsertintoDNAbetweenbasepairstepsHomoharringtonine,高三尖杉酯碱Alkaloid,生物碱Isolatedfromhomoharringtonineplant，三尖杉植物

Inhibitproteinsynthesis;DNAsynthesis中国协和医科院，黄量院士，国家科技进步一等奖四、Antitumorreagents–Topoisomeraseastargets作用于DNA拓扑异构酶的药物TopoisomerasescatalyzeandguidetheunknottingofDNAbycreatingtransientbreaksintheDNAusingaconservedTyrosineasthecatalyticresidueTopIandTopII:differentfunction（一）Camptothecin（喜树碱）,Hydroxycamptothecin（羟基喜树碱）TopisomeraseIinhibitors

CamptothecinisanaturalproductAdditionofthehydroxylanddimethylaminomethylgroupsimprovedwatersolubilityandreducedtheoccurrenceofunpredictablesideeffects

MechanismofAction:causesinglestrandbreaksinDNA（二）Anthracyclines（阿霉素类属蒽醌类）TopoisomeraseIIinhibitors

Atetracyclic

quinonecontainingringnucleustowhichisattachedauniquedaunosaminesugarReddishincolorFirstisolatedfromthefermentationbrothsofStreptomyces

peucetiusMechanismofAction:1)TheflattopographyoftheanthroquinonenucleusresultsintheabilityoftheanthracyclinestointercalatewithDNAperpendiculartoitslongaxis.2)Theanthroquinoneringsystemarecapableofgeneratingreactiveoxygenspecies,thefreeradicalsmayproducedestructiveeffectsuponthecellwhichmayincludedamagetotheDNATheaminosugarconfersaddedstabilitytothisbindingthroughitsinteractionwiththesugarphosphatebackboneofDNA阿霉素柔毛霉素表柔比星，表阿霉素OtherAnthracyclinesAnalogsSectionIIIAntimetaboliteantitumoragents第三节干扰ＤＮＡ合成的药物

Antimetabolitesarecompoundsthatpreventthebiosynthesisofnormalcellularmetabolites.Usually,thissuggestsaclosechemicalsimilaritybetweenthenaturalmetaboliteandtheantimetabolite.NarrowAntitumorSpectrum,normallyeffectiveforleukemia（白血病）一、PyrimidineAntimetabolites（嘧啶拮抗物）5-Fluorouracil,5-FU.ApyrimidinewithringmodificationsSometumorspreferentiallyuseuracilforpyrimidinebiosynthesisKeyintermediatesinthesynthesisofdeoxythymidylicacidfromdeoxyuridylicacid胸腺嘧啶脱氧核甙酸5-FdUMPbindstothymidylatesynthetasetogiveanintermediatethatresemblestheintermediateformedwithuridylicacid,however,thisintermediatecannotbreakdownandtheenzymeisinhibited胸腺嘧啶脱氧核甙酸合成酶

Metabolismof5-fluorouracilSynthesisof5-FUbaseRingopenproductStabilityinNaHSO3

（二）Cytarabine（ARA-C,阿糖胞苷）

Pyrimidineantimetaboliteinwhichsugarismodified

胞嘧啶衍生物

胞嘧啶阿拉伯糖Thenormal2’configurationisα主要用于治疗急性粒细胞白血病MetabolicactivationandinactivationofARA-C阿糖胞苷在体内的代谢激活与失活InactivespeciesMechanismofActionforARA-C

ARA-CTPinhibitstheconversionofcytidylicacidto2’-deoxycytidylicacid

ARA-CTP抑制磷酸胞苷转换为脱氧磷酸胞苷ARA-CTPalsoinhibitsDNA-dependentDNApolymerase

抑制依赖DNA的DNA多聚酶

ARA-CcausesmiscodingafterbeingincorporatedintoDNA

掺入DNA后编码错误，DNA合成终止SynthesisofCytarabineD-阿拉伯糖氰胺2-氨基-D-阿糖噁唑啉cyclocytidine氯代丙烯氰二、PurineAntimetabolites（嘌呤拮抗剂）巯嘌呤Poorwatersolubility主要用于各种急性白血病的治疗Na2SO3/H2ONa+6-MPMPinhibitsseveralkeyenzymesinvolvedinthebiosynthesisofpurineTheoverallactionof6-MPisinhibitionofthedenovosynthesisofpurinesMechanismofActionof6-mercaptopurineSynthesisofMercaptopurine硫脲三、Folicacidantimetabolites（叶酸拮抗剂）Folicacid,叶酸FolicacidisanessentialcomponentforthebiosynthesisofDNAandRNA叶酸是核酸生物合成的关键组分Animportantfactorforredcelldevelopment是红细胞发育生长的重要因子Pterine，Pteridoxamine，碟呤MTXcompeteswiththenormalsubstratefolicacid,inhibitsDNAsynthesis

Folicacidantimetabolites（叶酸拮抗剂）叶酸氨基碟呤，白血宁甲氨碟呤，MTXOtherAnticancerDrugs1.Taxol,orPaclitaxel（紫杉烷）AntimicrotubleAgentTaxolpromotestheassemblyofmicrotubulesfromtubulindimersFormula：C47H51NO14。MW：853.92，1971年

PacificYew，1967红豆杉Ovarian,breast,lungandcoloncancerMonroeE.WallTaxol®CamptothecinTMRTI，NCMansukhC.Wani2008，KetteringPrize--thehighesthonorinthefieldofcancerresearch1992年美国政府将专利转让给施贵宝（BMS），紫杉醇面世。1994年紫杉醇创世界抗癌药物全球销量冠军。2000年紫杉醇销量创百亿（后受原料供应未有进一步上升）2004年施贵宝专利到期，全球更多药厂介入紫杉醇生产。2005年中央再次发文，全国普查红豆杉资源，鼓励种植。2005年此项目接受个人投资者投资。2.Antiapoptoticproteininhibitors—ABT737Abott