《抗肿瘤药》讲义

1、抗肿瘤药讲义1ANTINEOPLASTIC AGENTS（抗肿瘤药）（抗肿瘤药）抗肿瘤药讲义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 agent

2、s （抗肿瘤药物的新靶点）（抗肿瘤药物的新靶点）抗肿瘤药讲义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 “cancer

3、ous tumor” is a malignant neoplasm with potential danger.抗肿瘤药讲义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 ca

4、ncer that arises from mesodermal tissue is called sarcoma. . 抗肿瘤药讲义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. 抗肿瘤药讲义6BlastomaThe s

5、uffix-blastomais used to indicate certain 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.抗肿瘤药讲义7Cell growth cycles In a cells nucleus, DNA replication occurs during onl

6、y one specific part of the cell cycle, called 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 cop

7、ies separate. 抗肿瘤药讲义8 Although each of these four 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 die抗肿瘤药讲义9抗肿瘤药讲义10SECTON 2 Agents direc

8、tly acting on DNA（作用于（作用于DNA的药物）的药物）I Alkylating agents （烷化剂）（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)的药物的药物抗肿瘤药讲义11I Alkylating agentsAlkylating agents are reactive compounds that act on DNA, RNA, and certain enzymes. 1. Nitrogen mustards

9、2. Aziridines3. Methanesulfonate esters and multiple alcohols 4. Nitrosoureas5. Triazemylimidazole6. Hydrazine derivatives）抗肿瘤药讲义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NCH2CH2ClCH2CH2ClRSCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClH抗肿瘤药讲义13Mechanism of nitrogen mustar

10、dsNCH2CH2ClCH2CH2ClR N+CH2CH2CH2ClRH2C N+CH2CH2CH2XRH2CX-NCH2CH2XCH2CH2ClR-Cl-Cl-Y-NCH2CH2XCH2CH2YR抗肿瘤药讲义14NNNNNH2HadenineHNNNNOHH2NguanineHNNOHOHNNOHCH3ONNNH2HOcytosineuracilthymine抗肿瘤药讲义15 Many derivatives of the nitrogen mustards have been synthesized with various improvements. These agents are t

11、hought to react with 7 position of guanine in each of the double strands of DNA, causing cross-linking, which interferes with separation of the strands and prevents mitosis.抗肿瘤药讲义16 The principle use of mechlorethamine is in combination chemotherapy of Hodgkins disease and the non-Hodgkins lymphomas

12、. It has wide activity, but more recent agents are safer and easier to use. A major disadvantage 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) Mech

13、lorethaminoxideHydrochloride(盐酸氧氮芥盐酸氧氮芥)*抗肿瘤药讲义17Chlorambucil Chlorambucil is used chiefly in chronic 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(CH2CH2C

14、l)2(CH2)3HOOC抗肿瘤药讲义18*Melphalan It is effective in multiple myeloma(骨髓瘤)and has had a role in the treatment of breast and ovarian cancers.*Formylmerphalan ()-N-Formyl-4-bis-(b b-chloroethyl)amino-phenylalanine（国产）降低毒性N(CH2CH2Cl)2CH2CHHOOCNH2CH2NCHCOOHNHCHOClCH2CH2ClCH2CH2抗肿瘤药讲义19Synthetic route of n

15、itrogen mustardsNRCH2CH2ClCH2CH2ClSOCl2NRCH2CH2OHCH2CH2OH抗肿瘤药讲义20*Cyclophosphamide (环磷酰胺环磷酰胺)N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide monohydrateH2OPNClCH2CH2ClCH2CH2ONOH抗肿瘤药讲义21Ifosfamide (异环磷酰胺异环磷酰胺) Trofosfamide (曲磷胺曲磷胺)PO(ClCH2CH2)2NCH2CH2ClNOPOClCH2CH2NHCH2CH2Cl

16、NO抗肿瘤药讲义222. 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)NNNNNNCH2H2CH2CH2CCH2CH2NNNNNNCH3H3CCH3CH3H3CH3Cp472抗肿瘤药讲义23Tepa *Thiotepa(替哌替哌) (塞替哌塞替哌) PSNNNPONNN抗肿瘤药讲义24*Mitomycin C (丝裂霉素丝裂霉素C) Mitomycin C contains three groups that can

17、 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）.OOH2NCH3NOCNH2NHOCH3O抗肿瘤药讲义25Reaction scheme for bioreductive activation of mitomycin C and the subsequent interstrand cross-linking of DNA.DNA- CH3OH2H+e-, Enzym

18、eHetcHO2+OOH2NCH3NNHDNAO2DNAOHOHH2NCH3NNHOHOHH2NCH3NOCNH2NHOOHOHH2NCH3NOCNH2NHOCH3OO-O-H2NCH3NOCNH2NHOCH3OOOH2NCH3NOCNH2NHOCH3O抗肿瘤药讲义263. Methanesulfonate esters 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)4OSOOC

19、H3抗肿瘤药讲义27Dibromomannitol 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水卫矛醇双乙酰化物): R=-COCH3H2CCOHCHCORHOROCH2CCCBrCH2HOHCHOH HOHCCH2BrOHHCCBrCH2HOHCOHHHOHCCH2BrHOH抗肿瘤药讲义28*Carmustine, BCNU（卡莫司汀卡莫司汀,卡氮芥）卡氮芥）CNH

20、NCH2CH2ClClH2CH2CNOON,N-Bis(2-chloroethyl)-N-nitrosourea4. Nitrosoureas（亚硝基脲类）（亚硝基脲类）抗肿瘤药讲义29* Synthetic route of Carmustine (BCNU,卡莫司汀卡莫司汀,卡氮芥卡氮芥)NCClCH2CH2NONHCH2CH2ClOHCOOHNaNO2DMFH2NCH2CH2OHNHOOCH2NH2NOHOCH2CH2NHCONHCH2CH2OHSOCl2HOCH2CH2NH2+CClCH2CH2NHClCH2CH2NHO抗肿瘤药讲义30Lomustine (CCNU, 洛莫司汀洛莫司汀

21、) : 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=ClCH2CH2NNOCNHROCH3CH2NNNH2CH3CH2OOHOHOHOCH3抗肿瘤药讲义31Decomposition of chloroethylnitrosoureas.ClCH2CH2NNOCNHROClCH2CH2NN OHCNRO+ClCH2CH2+N2+OH-carbamoylationalkylation氨甲酰化抗肿瘤药讲义32Streptozotocin (链左托星链左托

22、星): R=CH3Chlorozotocin (DCNU,氯脲霉素氯脲霉素): R=CH2CH2ClCH2OHOOHOHHNHCONROHNO抗肿瘤药讲义335. 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临床用于黑色素病，何杰金氏病的治疗NNNNNCH3CH3CONH2H抗肿瘤药讲义34Bioactivation of dacarbazine.NNNH2CONH2HNNNHNNCH3CONH2HNNNN

23、NHCH3CONH2HNNNNNCH3CH3CONH2HNNNNNCH2OHCH3CONH2H+HCHOCO2+OH-,NN+CH3orCH2N2N2+CH3+H+ 肝氧化酶系非酶水解抗肿瘤药讲义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-p-toluamide hydrochloride)CNHCHCH3NHNHCH2CH3CH3O. HCl抗肿瘤药讲义36Bioactivation of Procarbazi

24、ne 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CNHCHNCHCH3CH3OCH3NOOHCNHCHNCH2CH3CH3OCH3NO肝微粒体肝微粒体烷化烷基化p479抗肿瘤药讲义37II Platinum Complex (金属铂配

25、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 single agent against ovarian cancer. Other application include treatment of squam

26、ous and transitional cell carcinomas, and treatment of small-cell lung cancer.PtH3NH3NClCl抗肿瘤药讲义38III Bleomycin (博来霉素类博来霉素类) Bleomycin is a group of glycopeptides, with antitumor activity, isolated from Streptomyces verticillus（放线菌）（放线菌）. The clinical prepration is a mixture of bleomycin A2, A2I, B1

27、-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 sclerotherapy, as well as in combination therapies, especially because it la

28、cks bone marrow toxicity and immune suppression. It has modest activity in a variety of squamous cell cancer.抗肿瘤药讲义39Bleomycin A2: X= Bleomycin B2: X= Bleomycin A5: X=NNCH3H2NNHNHONHNH2NH2OOHHNH2HOCH3HHHOCH3HNHNHHOHOCH3HNSSNXOONHNHOHOHOHOOOHOHOHOOONH2OS+(CH3)2X-NHNHNNH2NHHHNNHNH2p482抗肿瘤药讲义40Antitumo

29、r mechanism of Bleomycin. p4843GCGAAATTTCGC5CGCTTTAAAGCGO2BLMFe(II)HNNOOCH3HCHOOCH2COOHPOOO-CG+HNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHOOHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGOHOO-POO-OT3A3GCGOHCOCH3CGO-OOPOOOONHN+抗肿瘤药讲义412. Agents acting on TopoII (作用于作用于T

30、opo 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吩噁嗪环抗肿瘤药讲义42 Actinomycin is the most active of a series of

31、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 binds with DNA by intercalationinsertion betwe

32、en 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, elongating the DNA.抗肿瘤药讲义43p486抗肿瘤药讲义44Doxorubicin

33、(Adriamycin，多柔比星，阿，多柔比星，阿霉素霉素)OOOOHOHCH2OHOOHOCH3OHNH2OCH3123456789101112131412345抗肿瘤药讲义45*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)OOOOHOHCH3OOHOCH3OHNH2OCH3OOOOHOHCH2OHOOHOCH3HONH2OCH3抗肿瘤药讲义46 Anthracyclines （蒽环类抗肿瘤抗生素）（蒽环类抗肿瘤抗生素）represents a major class of antineoplastic

34、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 treatment of solid tumors

35、such as carcinoma of the breast, lung, thyroid, and ovary, as well as soft tissue sarcomas.抗肿瘤药讲义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)2OCH3COOCH3CH3OOHOOCH3O抗肿瘤药讲义48* Mitoxantrone (Novantrone，米托蒽醌，米托蒽醌) 1,4-dihydro-5,8-bis2-

36、(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)2OHHCNNHHNNHCNNHHNN抗肿瘤药讲义49 SECTION 3 Agents interfering with DNA synthesisI Pyrimidine antagonists II P

37、urines antagonistsIII Folic Acid Antagonists抗肿瘤药讲义50I 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)-pyrimidinedioneHNNOHFO抗肿瘤药讲义51 Fluorouracil must be phosphorylated to the nucleotide to be active and, as such,

38、 inhibits 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 sy

39、nthesis 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.抗肿瘤药讲义52Antitumor Mechanism of Fluorouracil.HNNORFPdO+Nu-EnzHNNO-RFPdONu EnzNNNNNCOGluOHH2NHNNNNNCOGluOHH2NCH2HNOO