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性質，選用不同載體，可提高選擇性和抗腫瘤活性。依據載體化學結構，可分為脂肪氮芥、芳香氮芥、氨基酸氮芥、雜環氮芥和甾體氮芥。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，烷基化歷程是雙分子親核取代反應，活潑的乙撐亞胺離子極易與細胞成分的親核中心起烷化作用，屬強烷化劑。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-磷雜環己烷-P-氧化物一水合物。Withabroadspectrumofanti-tumor。PhysicochemicalpropertiesofcyclophosphamideWhitecrystalorcrystallinepowder(失去結晶水即液化)Soluableinwater,unstableinaqueoussolutionandeasilyhydrolyze,easilydecomposeunderheatingcondition.Cyclophosphamideisaprodrug.在肝臟被活化，經非酶促的β-消除反應生成丙烯醛（膀胱毒性）、磷酰氮芥及去甲氮芥，三者都是較強的烷化劑。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進行氯代和磷酰化，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，結構包括氮芥和L-苯丙氨酸部分，氮芥部分在堿性水溶液中易水解，含有α－氨基酸結構，會發生茚三酮顯色反應，且有氨基酸兩性性質。氮芥類藥物是通過在體內轉變成乙撐亞胺中間體發揮烷化劑作用，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，生成碳正離子與生物大分子發生親核取代反應進行烷基化。Busulfan,alsoknownasMyleran,namedas:4-Butanedioldimethylsulfonate。Clinicalforthetreatmentofchronicmyeloidleukemia.多元醇類藥物主要是鹵代多元醇，進入體內后會形成雙環氧化物而產生烷化作用。二溴甘露醇(Dibromomannitol)、二溴衛矛醇(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定，在體內分解生成親電性基團，破壞DNA的結構。。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，欺騙性地摻入生物大分子，導致“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，對結腸癌、直腸的癌、胃癌等有效，是治療實體腫瘤的首選藥。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滴注給藥。Prodrugsofcytarabine:為了減輕體內的脫氨失活，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1000倍，幾乎是不可逆地和二氫葉酸還原酶結合，使二氫葉酸不能轉化為四氫葉酸，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.強酸條件下不穩定，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多個氨基酸的N孤對電子對體內銅、鐵、鋅等形成1：1配合物，配合物轉化為過渡態的活性物，DNA斷裂。二噻唑部分嵌入DNA與特定部位結合，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內酯生物堿，羥基喜樹堿是喜樹堿的羥基衍生物，由五個環稠和而成，A、B環是喹啉環，C環為吡咯環，D環為吡啶酮結構，E環是一個α-羥基內酯環。共有兩個氮原子：一個是內酰胺的氮原子，一個是喹啉的氮原子，堿性較弱，與酸不能形成穩定的鹽。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