第七章抗肿瘤药课件

16四月2024第七章抗肿瘤药Classificationbymechanism1.Alkylatingagents2.Antimetabolites3.Drugsinteferingwithsynthesisofproteinoftumorcells13.1Biologicalalkylatingagents1.Nitrogenmustards2.Ethyleneimines3.Sulfonatesandhalogenatedpolyols4.NitrosoureaBioalkylatingagentsarecytotoxicdrugs.Invivo,itisabletoformapositivechargedcarbon-ionorotheractiveelectrophilicgroups,andthentheelectrophilicionscombinecovalentlywithelectronrichgroups(suchasamino,sulfhydryl,hydroxyl,carboxyl,phosphate,etc.)ofthecellsofbiologicalmacromolecules(DNA,RNA,enzymes),leadtothebreakingofDNAmolecule,atlastresultinthedeathoftumor.However,bioalkylatingdrugsalsoinhibitthenormalcellswiththepropertyofrapidproliferationsuchasbonemarrowcells,intestinalepithelialcellsatsametime.Sothebioalkylatingagentshavemoreserioussideeffects,suchasnausea,vomiting,bonemarrowsuppressionandhairloss.Clinicalusuallyarecarryingoncombinedusewithotherdrugs.BiologicalalkylatingagentsGeneralformulaofnitrogenmustards（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.DifferentR：脂肪氮芥、芳香氮芥Alkylationprocess: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：Chlormethinehydrochloridepresentedstrongdestructiontotumorcells,butwithpoorselectivityandlargetoxicity.OnlyEffectiveforlymphoma,sostructuralmodificationisnecessary.Nitromin:Reducedthepossibilityofformationofethyleneimineforthereducedelectroniccloudonnitrogen.Nitrominislesstoxicity,butalsothereducedanti-tumoractivity.NCH3ClClO2.Aromaticnitrogenmustards:

Theintroductionofaromaticringledtoreductionofalkalescencebyreasonofconjugation,somechanismwaschanged,noformationofcyclicethyleneimineionbuttheformationofcarboncationintermediate.CyclophosphamideP-[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。PhysicochemicalpropertiesofcyclophosphamideWhitecrystalorcrystallinepowder(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。Cyclophosphamidehasabroadspectrumofanti-tumor,clinicalfortreatmentofmalignantlymphoma,acutelymphocyticleukemia,multiplemyeloma,lungcanceretc.Clinicalapplicationofcyclophosphamide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

Melphalan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。13.1.3Sulfonatesandhalogenatedpolyols13.1.4Nitrosoureas

N-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CarmustineN，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.SynthesisofCarmustine13.2AntimetabolitesInterferewithpyrimidine,purineandfolicacidforbiosynthesisofDNAoftumorcells,soinhibitingmetabolismoftumorcell,atlastleadingtothedeathoftumorcell.Classificationofantimetabolites1.pyrimidines2.purines3.Folicacids尿嘧啶掺入肿瘤组织的速度较其他嘧啶快，氟的原子半径与氢的原子半径相近，氟化物的体积与原化合物几乎相等，C—F键的稳定性在代谢过程中不易分解。氟尿嘧啶能在分子水平代替正常代谢物，欺骗性地掺入生物大分子，导致“致死合成”。Fluorouracilcanreplacenormalmetabolitesatthemolecularlevel,deceptivelyincorporatedofbiologicalmacromolecules,resultingin"Synthesisofdeath."

5-氟尿嘧啶，5-fluorouracil,5-FU5-氟-2,4（1H,3H）-嘧啶二酮5-fluoro-2,4(1H,3H)-pyrimidine-dione13.2.1Pyrimidines本品抗瘤谱比较广，对绒毛膜上皮癌及恶性葡萄胎有显著疗效，对结肠癌、直肠的癌、胃癌等有效，是治疗实体肿瘤的首选药。Fluorouracilhasbroadspectrumofanti-tumor,significanteffectivetochoriocarcinomaandmalignantmole,effectivetocolorectalcancer,rectalcancer,stomachcancer,isthefirstchoiceforthetreatmentofsolidtumor.ClinicalapplicationofFluorouracilSynthesisoffluorouracil巯嘌呤Mercaptopurine6-Mercaptopurinemonohydrate用于各种急性白血病的治疗，对绒毛膜上皮癌及恶性葡萄胎也有效。Forthetreatmentofavarietyofacuteleukemias,alsoeffectivetochorionicepithelialcancerandmalignantmole.磺巯嘌呤钠增加了药物的水溶性。遇酸性和巯基化合物均易释放出6-MP，对肿瘤组织有一定的选择性。Tisupurineismorewater-solublethanmercaptopurine(6-MP).Easilyrelease6-MPunderacidicconditionortheexistingofsulfhydrylcompounds,hasselectivitytotumortissue.磺巯嘌呤钠TisupurineSynthesisoftisupurine盐酸阿糖胞苷Cytarabinehydrochloride1-β-D-呋喃型阿拉伯糖胞嘧啶盐酸盐1-β-D-arabinofuranosylcytosinehydrochloride用于治疗急性粒细胞白血病。Clinicalmainlyforthetreatmentofacutemyeloidleukemia.Metabolismandstability:盐酸阿糖胞苷会迅速被肝脏中的胞嘧啶脱氨酶作用脱氨，生成无活性的尿嘧啶阿糖胞苷，故口服吸收较差，通常是通过静脉连续滴注给药。Prodrugsofcytarabine:为了减轻体内的脱氨失活，将其氨基酰化成前药，如依诺他滨、棕榈酰阿糖胞苷，抗肿瘤活性强而持久。甲氨蝶呤methotrexate4-[4[[(2,4-二氨基-6-蝶啶）-甲基]-N-甲胺基]-苯甲酰基]-L-谷氨酸4-[4[[(2,4-diamino-6-Pteridinyl)-methyl]-N-methylamino]-benzoyl]-L-glutamaicacid甲氨蝶呤是叶酸的拮抗剂，对二氢叶酸还原酶的亲和力比二氢叶酸强1000倍，几乎是不可逆地和二氢叶酸还原酶结合，使二氢叶酸不能转化为四氢叶酸，从而影响辅酶F的生成，抑制DNA和RNA的合成。Methotrexateisanantagonistoffolicacid,theaffinitytodihydrofolatereductaseis1000timesstrongerthandihydrofolate,almostirreversiblycombinedwithdihydrofolatereductase,sothatdihydrofolatecannotbetransformedintotetrahydrofolate,somethotrexateinterferewiththegenerationofcoenzymeF,inhibitingthebiosynthesisofDNAandRNAoftumorcells.Fortreatmentofacuteleukemia,chorioncellcarcinomaandmalignantmole.强酸条件下不稳定，酰胺键水解，生成谷氨酸和蝶呤酸而失去活性。Bleomycin,seperatedfromstreptomycesverticillus.BrokentheDNAchainstokilltumorbyactingontumorcelldirectly.13.3Naturalantitumoragents13.3.1Anti-tumorantibiotics多个氨基酸的N孤对电子对体内铜、铁、锌等形成1：1配合物，配合物转化为过渡态的活性物，DNA断裂。二噻唑部分嵌入DNA与特定部位结合，使DNA裂解。13.3.2TopoisomeraseⅠinhibitorsCamptothecinsactonDNAtopoisomeraseⅠ(TopoⅠ),effectivetodigestivetracttumor.10-羟基喜树碱(hydroxycamptothecin)喜树碱是从中国特有的珙桐科植物喜树中分离得到的第一个内酯生物碱，羟基喜树碱是喜树碱的羟基衍生物，由五个环稠和而成，A、B环是喹啉环，C环为吡咯环，D环为吡啶酮结构，E环是一个α-羟基内酯环。共有两个氮原子：一个是内酰胺的氮原子，一个是喹啉的氮原子，碱性较弱，与酸不能形成稳定的盐。CamptothecinisaDNAtopoisomeraseinhibitor,itsanti-cancermechanismisnotduetoinhibitionofenzymeactivity,butbyblockingthelaststepreactionbetweenenzymeandDNA,leadingtoDNAbreakageandcelldeath.放线菌D（更生霉素）(dactinomycin)DactinomycinistheembeddedtopoisomeraseⅡinhibitor.13.3.3TopoisomeraseⅡinhibitors阿霉素（多柔比星）(doxorubicin)Doxorubicinisananthraquinoneanti-tumorantibiotic,ageneralantineoplasticagent.orangeneedlecrystal,stableinaqueoussolutionandinstableunderalkalineconditionandbeeasytodecompose,withsideeffectofbonemarrowsuppressionandcardiactoxicity.Mechanisms:embeddedtopoisomeraseⅡinhibitor,embeddingamongDNAmolecules.NonembeddedToPoⅡinhibitor:切断DNA双链，不嵌入.podophyllotoxinMechanism:作