16四月2024第七章抗腫瘤藥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：可以改善藥物藥代動力學(xué)性質(zhì)，選用不同載體，可提高選擇性和抗腫瘤活性。依據(jù)載體化學(xué)結(jié)構(gòu)，可分為脂肪氮芥、芳香氮芥、氨基酸氮芥、雜環(huán)氮芥和甾體氮芥。13.1.1NitrogenmustardsMechlorethaminehydrochlorideN-甲基-N-（2-氯乙基）-2-氯乙胺鹽酸鹽N-methyl-N-(2-chloroethyl)-2-chloroethylaminehydrochlorideClinicalapplication:mainlytreatmentforlymphosarcomaandHodgkin'sdiseaseDevelopment:duringtheFirstWorldWar,nitrogenmustardwasusedasatoxicgas,shortlyafteritwasfoundthepropertyofinhibitingbonemarrowandlymphoidtissueofthevictims.In1942,GilmanfromYaleUniversityfirstlyusednitrogenmustardinthetreatmentoflymphoidneoplasms.DifferentR：脂肪氮芥、芳香氮芥Alkylationprocess:脂肪氮芥的氮原子堿性比較強(qiáng)，烷基化歷程是雙分子親核取代反應(yīng)，活潑的乙撐亞胺離子極易與細(xì)胞成分的親核中心起烷化作用，屬強(qiáng)烷化劑。Itisusuallyusedasinjectiondrugofaqueoussolution,whichpHvaluemaintainedat3.0~5.0.Stability：Chlormethinehydrochloridepresentedstrongdestructiontotumorcells,butwithpoorselectivityandlargetoxicity.OnlyEffectiveforlymphoma,sostructuralmodificationisnecessary.Nitromin:Reducedthepossibilityofformationofethyleneimineforthereducedelectroniccloudonnitrogen.Nitrominislesstoxicity,butalsothereducedanti-tumoractivity.NCH3ClClO2.Aromaticnitrogenmustards:

Theintroductionofaromaticringledtoreductionofalkalescencebyreasonofconjugation,somechanismwaschanged,noformationofcyclicethyleneimineionbuttheformationofcarboncationintermediate.CyclophosphamideP-[N，N-雙-（β-氯乙基）]-1-氧-3-氮-2-磷雜環(huán)己烷-P-氧化物一水合物。Withabroadspectrumofanti-tumor。PhysicochemicalpropertiesofcyclophosphamideWhitecrystalorcrystallinepowder(失去結(jié)晶水即液化)Soluableinwater,unstableinaqueoussolutionandeasilyhydrolyze,easilydecomposeunderheatingcondition.Cyclophosphamideisaprodrug.在肝臟被活化，經(jīng)非酶促的β-消除反應(yīng)生成丙烯醛（膀胱毒性）、磷酰氮芥及去甲氮芥，三者都是較強(qiáng)的烷化劑。Cyclophosphamidehasabroadspectrumofanti-tumor,clinicalfortreatmentofmalignantlymphoma,acutelymphocyticleukemia,multiplemyeloma,lungcanceretc.Clinicalapplicationofcyclophosphamide以二乙醇胺作為原料，用過量的三氯氧磷同時(shí)進(jìn)行氯代和磷酰化，制得氮芥磷酰二氯，再與3-氨基丙醇縮合。Synthesisofcyclophosphamide美法侖

Melphalan氮芥類的烷化劑，結(jié)構(gòu)包括氮芥和L-苯丙氨酸部分，氮芥部分在堿性水溶液中易水解，含有α－氨基酸結(jié)構(gòu)，會發(fā)生茚三酮顯色反應(yīng)，且有氨基酸兩性性質(zhì)。氮芥類藥物是通過在體內(nèi)轉(zhuǎn)變成乙撐亞胺中間體發(fā)揮烷化劑作用，乙撐亞胺的磷酰胺衍生物，可提高抗腫瘤作用及減小毒性。Tepawasclinicalusedfortreatmentofleukaemi。Thiotepachangedintotepainvivo.Clinicalforthetreatmentofbreastcancer,ovariancancer,bladdercancer,andsoon.13.1.2EthyleneiminesTepaThiotepaSulfonatesandhalogenatedpolyolsarenon-nitrogenmustardalkylatingagents。甲磺酸酯是較好的離去基團(tuán)，生成碳正離子與生物大分子發(fā)生親核取代反應(yīng)進(jìn)行烷基化。Busulfan,alsoknownasMyleran,namedas:4-Butanedioldimethylsulfonate。Clinicalforthetreatmentofchronicmyeloidleukemia.多元醇類藥物主要是鹵代多元醇，進(jìn)入體內(nèi)后會形成雙環(huán)氧化物而產(chǎn)生烷化作用。二溴甘露醇(Dibromomannitol)、二溴衛(wèi)矛醇(Dibromodulcilol)等。13.1.3Sulfonatesandhalogenatedpolyols13.1.4Nitrosoureas

N-亞硝基的存在使該氮原子與鄰近羰基之間的鍵變得不穩(wěn)定，在體內(nèi)分解生成親電性基團(tuán)，破壞DNA的結(jié)構(gòu)。。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’-雙（β-氯乙基)-N-亞硝基脲，又名卡氮芥N,N'-bis-(β-chloroethyl)-N-nitrosoureaCarmustineishighlylipophilic,easilypassthroughtheblood-brainbarrierforthetreatmentofbraintumors,othercentralnervoussystemtumorsandmalignantlymphoma.SynthesisofCarmustine13.2AntimetabolitesInterferewithpyrimidine,purineandfolicacidforbiosynthesisofDNAoftumorcells,soinhibitingmetabolismoftumorcell,atlastleadingtothedeathoftumorcell.Classificationofantimetabolites1.pyrimidines2.purines3.Folicacids尿嘧啶摻入腫瘤組織的速度較其他嘧啶快，氟的原子半徑與氫的原子半徑相近，氟化物的體積與原化合物幾乎相等，C—F鍵的穩(wěn)定性在代謝過程中不易分解。氟尿嘧啶能在分子水平代替正常代謝物，欺騙性地?fù)饺肷锎蠓肿樱瑢?dǎo)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本品抗瘤譜比較廣，對絨毛膜上皮癌及惡性葡萄胎有顯著療效，對結(jié)腸癌、直腸的癌、胃癌等有效，是治療實(shí)體腫瘤的首選藥。Fluorouracilhasbroadspectrumofanti-tumor,significanteffectivetochoriocarcinomaandmalignantmole,effectivetocolorectalcancer,rectalcancer,stomachcancer,isthefirstchoiceforthetreatmentofsolidtumor.ClinicalapplicationofFluorouracilSynthesisoffluorouracil巰嘌呤Mercaptopurine6-Mercaptopurinemonohydrate用于各種急性白血病的治療，對絨毛膜上皮癌及惡性葡萄胎也有效。Forthetreatmentofavarietyofacuteleukemias,alsoeffectivetochorionicepithelialcancerandmalignantmole.磺巰嘌呤鈉增加了藥物的水溶性。遇酸性和巰基化合物均易釋放出6-MP，對腫瘤組織有一定的選擇性。Tisupurineismorewater-solublethanmercaptopurine(6-MP).Easilyrelease6-MPunderacidicconditionortheexistingofsulfhydrylcompounds,hasselectivitytotumortissue.磺巰嘌呤鈉TisupurineSynthesisoftisupurine鹽酸阿糖胞苷Cytarabinehydrochloride1-β-D-呋喃型阿拉伯糖胞嘧啶鹽酸鹽1-β-D-arabinofuranosylcytosinehydrochloride用于治療急性粒細(xì)胞白血病。Clinicalmainlyforthetreatmentofacutemyeloidleukemia.Metabolismandstability:鹽酸阿糖胞苷會迅速被肝臟中的胞嘧啶脫氨酶作用脫氨，生成無活性的尿嘧啶阿糖胞苷，故口服吸收較差，通常是通過靜脈連續(xù)滴注給藥。Prodrugsofcytarabine:為了減輕體內(nèi)的脫氨失活，將其氨基酰化成前藥，如依諾他濱、棕櫚酰阿糖胞苷，抗腫瘤活性強(qiáng)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甲氨蝶呤是葉酸的拮抗劑，對二氫葉酸還原酶的親和力比二氫葉酸強(qiáng)1000倍，幾乎是不可逆地和二氫葉酸還原酶結(jié)合，使二氫葉酸不能轉(zhuǎn)化為四氫葉酸，從而影響輔酶F的生成，抑制DNA和RNA的合成。Methotrexateisanantagonistoffolicacid,theaffinitytodihydrofolatereductaseis1000timesstrongerthandihydrofolate,almostirreversiblycombinedwithdihydrofolatereductase,sothatdihydrofolatecannotbetransformedintotetrahydrofolate,somethotrexateinterferewiththegenerationofcoenzymeF,inhibitingthebiosynthesisofDNAandRNAoftumorcells.Fortreatmentofacuteleukemia,chorioncellcarcinomaandmalignantmole.強(qiáng)酸條件下不穩(wěn)定，酰胺鍵水解，生成谷氨酸和蝶呤酸而失去活性。Bleomycin,seperatedfromstreptomycesverticillus.BrokentheDNAchainstokilltumorbyactingontumorcelldirectly.13.3Naturalantitumoragents13.3.1Anti-tumorantibiotics多個(gè)氨基酸的N孤對電子對體內(nèi)銅、鐵、鋅等形成1：1配合物，配合物轉(zhuǎn)化為過渡態(tài)的活性物，DNA斷裂。二噻唑部分嵌入DNA與特定部位結(jié)合，使DNA裂解。13.3.2TopoisomeraseⅠinhibitorsCamptothecinsactonDNAtopoisomeraseⅠ(TopoⅠ),effectivetodigestivetracttumor.10-羥基喜樹堿(hydroxycamptothecin)喜樹堿是從中國特有的珙桐科植物喜樹中分離得到的第一個(gè)內(nèi)酯生物堿，羥基喜樹堿是喜樹堿的羥基衍生物，由五個(gè)環(huán)稠和而成，A、B環(huán)是喹啉環(huán)，C環(huán)為吡咯環(huán)，D環(huán)為吡啶酮結(jié)構(gòu)，E環(huán)是一個(gè)α-羥基內(nèi)酯環(huán)。共有兩個(gè)氮原子：一個(gè)是內(nèi)酰胺的氮原子，一個(gè)是喹啉的氮原子，堿性較弱，與酸不能形成穩(wěn)定的鹽。CamptothecinisaDNAtopoisomeraseinhibitor,itsanti-cancermechanismisnotduetoinhibitionofenzymeactivity,butbyblockingthelaststepreactionbetweenenzymeandDNA,leadingtoDNAbreakageandcelldeath.放線菌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:切斷DNA雙鏈，不嵌入.podophyllotoxinMechanism:作