抗肿瘤药PT课件

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1、1ANTINEOPLASTIC AGENTS（抗肿瘤药）（抗肿瘤药）2SECTION 1 Introduction（概述）（概述）SECTION 2 Agents directly acting on DNA （作用于（作用于DNA的药物）的药物）SECTION 3 Agents interfering with DNA synthesis （干扰（干扰DNA合成的药物）合成的药物）SECTION 4 Antimitotic agents （抗有丝分裂的药物）（抗有丝分裂的药物）SECTION 5 New targets for antineoplastic agents （抗肿瘤药物的新靶点

2、）（抗肿瘤药物的新靶点）3SECTON 1 Introductionneoplasm（肿瘤）（肿瘤） The medical term for cancer or tumor is neoplasm（肿瘤）（肿瘤）, which means “a relatively autonomous growth of tissue.” Tumor is a general term indicating any abnormal mass or growth of tissue, not necessarily life-threatening. A “cancerous tumor” is a ma

3、lignant neoplasm with potential danger.4sarcoma In the early embryo of a multicellular organism before organs begin to form, cells arrange themselves in three layersectodermal, mesodermal, and endodermal. Mesodermal cells form bone, muscle, cartilage, and related tissues.A cancer that arises from me

4、sodermal tissue is called sarcoma. . 5carcinoma Ectodermal cells form skin, its appendages, and nerve tissue. Endodermal cells form the intestinal system and its associated organs A cancer arises from ecto- or endodermal cells is called a carcinoma. 6BlastomaThe suffix-blastomais used to indicate ce

5、rtain types of tumors that have primitive appearance resembling embryonic structures. Cancers of bloodA cancer of the blood involving abnormal increase of leukocytes is called leukemia.7Cell growth cycles In a cells nucleus, DNA replication occurs during only one specific part of the cell cycle, cal

6、led S for synthesis. Between division and S is a period called G1 in which cells grow, but do not make DNA. In G1, many molecules such as enzymes are synthesized. Another period called G2 occurs between S and the period called M, during which the two DNA copies separate. 8 Although each of these fou

7、r main periods of the cell cycle (G1, S, G2, M) is unique, all in proper order are necessary for new cell production. Normal and cancer cells behave differently. Normal cell: G1 G0 G1 Cancer cell: G1, S, G2, M G0 die910SECTON 2 Agents directly acting on DNA（作用于（作用于DNA的药物）的药物）I Alkylating agents （烷化剂

8、）（烷化剂）II Platinum Complex (金属铂配合物金属铂配合物)III Bleomycin (博来霉素类博来霉素类) IV 作用于作用于DNA拓扑异构酶拓扑异构酶(topoismerase)的药物的药物11I Alkylating agentsAlkylating agents are reactive compounds that act on DNA, RNA, and certain enzymes. 1. Nitrogen mustards2. Aziridines3. Methanesulfonate esters and multiple alcohols 4. N

9、itrosoureas5. Triazemylimidazole6. Hydrazine derivatives）12I Alkylating agents （烷化剂）（烷化剂）1. Nitrogen mustards（氮芥类）（氮芥类） 载体部分载体部分 烷基化部分烷基化部分NCH2CH2ClCH2CH2ClRSCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClH13Mechanism of nitrogen mustardsNCH2CH2ClCH2CH2ClR N+CH2CH2CH2ClRH2C N+CH2CH2CH2XRH2CX-NCH2CH2XCH2CH2ClR-Cl-

10、Cl-Y-NCH2CH2XCH2CH2YR14NNNNNH2HadenineHNNNNOHH2NguanineHNNOHOHNNOHCH3ONNNH2HOcytosineuracilthymine15 Many derivatives of the nitrogen mustards have been synthesized with various improvements. These agents are thought to react with 7 position of guanine in each of the double strands of DNA, causing c

11、ross-linking, which interferes with separation of the strands and prevents mitosis.16 The principle use of mechlorethamine is in combination chemotherapy of Hodgkins disease and the non-Hodgkins lymphomas. It has wide activity, but more recent agents are safer and easier to use. A major disadvantage

12、 ultimately carcinogenic, effect on bone marrow stem cells, culminating in a form of acute myelogenous leukemia.HClNCH2CH2ClCH2CH2ClCH3HClNCH2CH2ClCH2CH2ClCH3OMechlorethamine Hydrochloride (盐酸氮芥盐酸氮芥) MechlorethaminoxideHydrochloride(盐酸氧氮芥盐酸氧氮芥)*17Chlorambucil Chlorambucil is used chiefly in chronic

13、lymphocytic leukemia, usually orally because of its favorable aqueous solubility as the sodium salt and rapid conversion to the free drug. Side effects are anorexia厌食, nausea, and vomiting.N(CH2CH2Cl)2(CH2)3HOOC18*Melphalan It is effective in multiple myeloma(骨髓瘤)and has had a role in the treatment

14、of breast and ovarian cancers.*Formylmerphalan ()-N-Formyl-4-bis-(b b-chloroethyl)amino-phenylalanine（国产）降低毒性N(CH2CH2Cl)2CH2CHHOOCNH2CH2NCHCOOHNHCHOClCH2CH2ClCH2CH219Synthetic route of nitrogen mustardsNRCH2CH2ClCH2CH2ClSOCl2NRCH2CH2OHCH2CH2OH20*Cyclophosphamide (环磷酰胺环磷酰胺)N,N-Bis(2-chloroethyl)tetra

15、hydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide monohydrateH2OPNClCH2CH2ClCH2CH2ONOH21Ifosfamide (异环磷酰胺异环磷酰胺) Trofosfamide (曲磷胺曲磷胺)PO(ClCH2CH2)2NCH2CH2ClNOPOClCH2CH2NHCH2CH2ClNO222. Aziridines （乙撑亚胺类）（乙撑亚胺类）Tretamine Hexamethylmelamine(Triethylenemelamine, (HMM, 六甲蜜胺六甲蜜胺)TEM,三曲他胺三曲他胺,三乙蜜胺三乙蜜胺)NNNNNNC

16、H2H2CH2CH2CCH2CH2NNNNNNCH3H3CCH3CH3H3CH3Cp47223Tepa *Thiotepa(替哌替哌) (塞替哌塞替哌) PSNNNPONNN24*Mitomycin C (丝裂霉素丝裂霉素C) Mitomycin C contains three groups that can damage cells: the quinone that can participate in free radical reactions generating superoxides, and aziridinyl and urethane（乌拉坦,氨基甲酸乙酯）.OOH2NC

17、H3NOCNH2NHOCH3O25Reaction scheme for bioreductive activation of mitomycin C and the subsequent interstrand cross-linking of DNA.DNA- CH3OH2H+e-, EnzymeHetcHO2+OOH2NCH3NNHDNAO2DNAOHOHH2NCH3NNHOHOHH2NCH3NOCNH2NHOOHOHH2NCH3NOCNH2NHOCH3OO-O-H2NCH3NOCNH2NHOCH3OOOH2NCH3NOCNH2NHOCH3O263. Methanesulfonate e

18、sters and multiple alcohols （甲磺酸酯及多元醇类）（甲磺酸酯及多元醇类）*Busulfan (白消安，马利兰白消安，马利兰)双功能的烷化剂，临床对于慢性粒细胞白血病的疗效显双功能的烷化剂，临床对于慢性粒细胞白血病的疗效显著著SOCH3OO(CH2)4OSOOCH327Dibromomannitol Dibromodulcilol (二溴甘露醇二溴甘露醇) (DBD, 二溴卫矛醇二溴卫矛醇)Dianhydrogalactitol (DAG, 脱水卫矛醇脱水卫矛醇): R=HDiacetyl dianhydrogalactitol (DADAG, 脱水卫矛醇双乙酰化物脱

19、水卫矛醇双乙酰化物): R=-COCH3H2CCOHCHCORHOROCH2CCCBrCH2HOHCHOH HOHCCH2BrOHHCCBrCH2HOHCOHHHOHCCH2BrHOH28*Carmustine, BCNU（卡莫司汀卡莫司汀,卡氮芥）卡氮芥）CNHNCH2CH2ClClH2CH2CNOON,N-Bis(2-chloroethyl)-N-nitrosourea4. Nitrosoureas（亚硝基脲类）亚硝基脲类）29* Synthetic route of Carmustine (BCNU,卡莫司汀卡莫司汀,卡氮芥卡氮芥)NCClCH2CH2NONHCH2CH2ClOHCOOH

20、NaNO2DMFH2NCH2CH2OHNHOOCH2NH2NOHOCH2CH2NHCONHCH2CH2OHSOCl2HOCH2CH2NH2+CClCH2CH2NHClCH2CH2NHO30Lomustine (CCNU, 洛莫司汀洛莫司汀) : R=Semustine (Me-CCNU,司莫司汀司莫司汀) : R=Nimustine (ACNU,盐酸尼莫司汀盐酸尼莫司汀) : R=Ranimustine (雷莫司汀雷莫司汀): R=ClCH2CH2NNOCNHROCH3CH2NNNH2CH3CH2OOHOHOHOCH331Decomposition of chloroethylnitrosou

21、reas.ClCH2CH2NNOCNHROClCH2CH2NN OHCNRO+ClCH2CH2+N2+OH-carbamoylationalkylation氨甲酰化32Streptozotocin (链左托星链左托星): R=CH3Chlorozotocin (DCNU,氯脲霉素氯脲霉素): R=CH2CH2ClCH2OHOOHOHHNHCONROHNO335. Triazemylimidazole（三氮烯咪唑类）（三氮烯咪唑类） *Dacarbazine (DTIC, 达卡巴嗪达卡巴嗪) 5-(3,3-dimethyl-1-triazemyl)-imidazole-4-carboxamide

22、临床用于黑色素病，何杰金氏病的治疗NNNNNCH3CH3CONH2H34Bioactivation of dacarbazine.NNNH2CONH2HNNNHNNCH3CONH2HNNNNNHCH3CONH2HNNNNNCH3CH3CONH2HNNNNNCH2OHCH3CONH2H+HCHOCO2+OH-,NN+CH3orCH2N2N2+CH3+H+ 肝氧化酶系非酶水解356. Hydrazine derivatives（肼类）（肼类）*Procarbazine Hydrochloride (丙卡巴肼，甲基苄肼丙卡巴肼，甲基苄肼)N-isopropyl-(2-methyl-hydrazino

23、-p-toluamide hydrochloride)CNHCHCH3NHNHCH2CH3CH3O. HCl36Bioactivation of Procarbazine hydrochloride in vivo.烷基化烷化H2O. HClCNHCHCH3NHNHCH2CH3CH3OCNHCHNCH2CH3CH3OCH3NCNHCHNCH2CH3CH3OCH3NOCNHCHNCH2CH3CH3OHOCH2NO-H2OCH3N+NH2OCNHCHN+CH2CH3CH3ONNADPH , O2NADP-NADP-,NADPH , O2H2OP-450P-450细胞色素细胞色素CNHCHNCHCH

24、3CH3OCH3NOOHCNHCHNCH2CH3CH3OCH3NO肝微粒体肝微粒体烷化烷基化p47937II Platinum Complex (金属铂配合物金属铂配合物) *Cisplatin (顺铂顺铂) Cisplatin is the most active single agent against nonseminomatous(非精原细胞瘤的)testicular cancer, and combinated with vinblastine and bleomycin, it is usually curative. It is also the most active sing

25、le agent against ovarian cancer. Other application include treatment of squamous and transitional cell carcinomas, and treatment of small-cell lung cancer.PtH3NH3NClCl38III Bleomycin (博来霉素类博来霉素类) Bleomycin is a group of glycopeptides, with antitumor activity, isolated from Streptomyces verticillus（放

26、线菌）（放线菌）. The clinical prepration is a mixture of bleomycin A2, A2I, B1-4, etc, with A2 the predominant component. Bleomycin causes strand scission and fragment of DNA. It acts in the form of a cupric complex, inhibiting DNA ligase.Bleomycin hs been used in basal cell carcinoma and pericardial scler

27、otherapy, as well as in combination therapies, especially because it lacks bone marrow toxicity and immune suppression. It has modest activity in a variety of squamous cell cancer.39Bleomycin A2: X= Bleomycin B2: X= Bleomycin A5: X=NNCH3H2NNHNHONHNH2NH2OOHHNH2HOCH3HHHOCH3HNHNHHOHOCH3HNSSNXOONHNHOHOH

28、OHOOOHOHOHOOONH2OS+(CH3)2X-NHNHNNH2NHHHNNHNH2p48240Antitumor mechanism of Bleomycin. p4843GCGAAATTTCGC5CGCTTTAAAGCGO2BLMFe(II)HNNOOCH3HCHOOCH2COOHPOOO-CG+HNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHOOHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGOHOO-POO-OT3A3GCGOHCOCH

29、3CGO-OOPOOOONHN+412. Agents acting on TopoII (作用于作用于Topo II 的抗肿瘤药物的抗肿瘤药物)嵌入型抗肿瘤药物嵌入型抗肿瘤药物L-苏氨酸苏氨酸 D-缬氨酸缬氨酸 L-脯氨酸脯氨酸 N-甲基甘氨酸甲基甘氨酸 L-N-甲基缬氨酸甲基缬氨酸放线菌素放线菌素D p485(Actinomycin D, Dactinomycin)H3CCONOH3CCONH2ONHNHCHCHCOCOCHCHH3CH3COONHNHCHCHC3H7COCOC3H7NNCOCONNCH2CH3CH2COCONNCH3CHCHC3H7C3H7CH3CH3CCOO吩噁嗪环42

30、 Actinomycin is the most active of a series of cyclic pentapeptides isolated from Streptomyces parvulus. The chemical structure of the antibiotics is composed of a tricyclic, phenoxazin-3-one chromophore and two identical pentapeptide lactones group, a and b, attached to the chromophore. Actinomycin

31、 binds with DNA by intercalationinsertion between base pairs as in a sandwich, and perpendicular to the main axis of the helix, as are the base pairs. Because of its flat rigid aromatic structure, the oxazine（噁嗪）portion of actinomycin can bind nonconvalently between two successive bases in DNA, elon

32、gating the DNA.43p48644Doxorubicin (Adriamycin，多柔比星，阿，多柔比星，阿霉素霉素)OOOOHOHCH2OHOOHOCH3OHNH2OCH312345678910111213141234545*Daunorubicin Epirubicin(Daunomycin，柔红霉素，柔红霉素) (表柔比星，表阿霉素表柔比星，表阿霉素)OOOOHOHCH3OOHOCH3OHNH2OCH3OOOOHOHCH2OHOOHOCH3HONH2OCH346 Anthracyclines （蒽环类抗肿瘤抗生素）（蒽环类抗肿瘤抗生素）represents a major c

33、lass of antineoplastic drugs. Doxorubicin is probably the most important anticancer drug available because of its relatively broad spectrum of activity, and daunorubicin is an important agent in the treatment of acute lymphocytic and myelocytic leukemia. Doxorubicin has a significant role in the tre

34、atment of solid tumors such as carcinoma of the breast, lung, thyroid, and ovary, as well as soft tissue sarcomas.47Zorubicin Aclacinomycin A (佐柔比星佐柔比星) (阿柔比星，阿克拉霉素阿柔比星，阿克拉霉素) OCH3OOOHOHNCH3OHOOCH3ONH2HNHCC6H5OHOHOOOHOHOON(CH3)2OCH3COOCH3CH3OOHOOCH3O48* Mitoxantrone (Novantrone，米托蒽醌，米托蒽醌) 1,4-dihydr

35、o-5,8-bis2-(2-hydroxyethyl)amino-ethyl-amino9,10-anthracenedinone Bisantrene (比生群比生群)Two anthracene derivatives showed low toxicity, andespecially low cardiac toxicity.OHOHOONH(CH2)2NH(CH2)2OHNH(CH2)2NH(CH2)2OHHCNNHHNNHCNNHHNN49 SECTION 3 Agents interfering with DNA synthesisI Pyrimidine antagonists

36、 II Purines antagonistsIII Folic Acid Antagonists50I Pyrimidine antagonists（嘧啶拮抗物）（嘧啶拮抗物） 1. Uracil derivatives（尿嘧啶衍生物）（尿嘧啶衍生物） Fluorouracil (5-FU，氟脲嘧啶，氟脲嘧啶，5-氟尿嘧啶氟尿嘧啶)5-fluoro-2,4(1H,3H)-pyrimidinedioneHNNOHFO51 Fluorouracil must be phosphorylated to the nucleotide to be active and, as such, inhibi

37、ts thymidylate(胸苷酸)synthetase, a key enzyme in the biosynthesis of DNA. It has at least two biochemical actions that may account for its cytotoxicity. It is converted first to the monophosphates 5-FUMP and 5-FdMP; the latter binds tightly to thymidylate synthetase and inhibits the eventual synthesis

38、 of DNA. On the other hand, 5-FUMP, after conversion to 5-FUTP, is incorporated into RNA and inhibits RNA processing of mRNA and rRNA, and may cause errors in base pairing during RNA transcription.52Antitumor Mechanism of Fluorouracil.HNNORFPdO+Nu-EnzHNNO-RFPdONu EnzNNNNNCOGluOHH2NHNNNNNCOGluOHH2NCH

39、2HNOONuRPdFEnzHHHNNORCH3PdO+HH2NOHCOGluNNNNNHNu-Enz脱氧氟尿嘧啶核苷酸胸腺嘧啶合成酶+53Hydrolysis of Fluorouracil .O-NNH2OSO3-OFHOH-O-HOHFOHNNOFOSO3-HHSO3-OH-或O-NNH2OHOFH-SO32-FHNNOHOSO3-HHNNOFOHKE+HNNOFOH54II Purines antagonists (嘌呤拮抗物嘌呤拮抗物)*6-Mercaptopurine HypoxanthineNNNNSHHNNNNOHH55 6-MP is inactive until metab

40、olized to their respective monophosphate ribonucleotides, which result from action of the enzyme hypoxanthine-guanine phosphoribosyl transferase (HGPRTase). The monophosphates can inhibit de novo purine synthesis, i. e., the formation of adenylic and guanylic acides from inosinic acid . Further phos

41、phorylation gives the triphosphate nucleotides.56 Sulfomercaprine Sodium (磺巯嘌呤钠，溶癌呤磺巯嘌呤钠，溶癌呤)Sodium 6-mercaptopurine-S-sulfonate dihydrate2 H2ONNNNSNaSO3Na57磺巯嘌呤钠与巯嘌呤的合成路线磺巯嘌呤钠与巯嘌呤的合成路线Na2CO3 , NiHCOOH(O)H2ONa2SO3I2PS5Na2S2O4 , NaOHNaNO2 , HClC2H5OHC2H5ONa6-MP+2H2ONNNNSSO3NaNaNNNNSSNNNNHHNNNNOHHNNOH

42、NH2NH2NNOHHSNH2NH2NNOHHSNH2NONNOHHSNH2CH2COOC2H5CN+CNH2SNH2NNNNSHH58 Azathioprine 6-Thioguanine Pentostatin (6-AP, 硫唑嘌呤硫唑嘌呤) (6-TG, 硫鸟嘌呤硫鸟嘌呤) (喷司他丁喷司他丁)NNNNSHH2NHNNNNSNNCH3O2NHNNNHNHOHOOHOH口服吸收良好对腺苷酸脱氨酶有抑制作用59III Folic Acid Antagonists (叶酸拮抗物叶酸拮抗物)Folic Acid (叶酸叶酸)Aminopterin (氨基蝶呤，白血宁氨基蝶呤，白血宁)NNNNC

43、H2H2NOHNHCONHCHCH2CH2COOHCOOHNNNNCH2H2NNH2NHCONHCHCH2CH2COOHCOOH60*Methotrexate (MTX, 甲氨蝶呤甲氨蝶呤)N-4-2,4-diamino-6-pteridinylmethylmethyl-amino-benzoyl-L-glutamic acid Methotrexate acts as an antifolate by binding almost irreversibly to the enzyme dihydrofolate reductase and preventing the formation of the coenzyme tetrahydrofolic acids, essential for DNA synthesis and for replication of animal cells.NNNNCH2H2NNH2NCH3CONHCHCH2CH2COOHCOOH1234567