《抗腫瘤藥》ppt課件

1、ANTINEOPLASTIC AGENTS抗腫瘤藥抗腫瘤藥SECTION 1 Introduction概述概述SECTION 2 Agents directly acting on DNA 作用于作用于DNA的藥物的藥物SECTION 3 Agents interfering with DNA synthesis 干擾干擾DNA合成的藥物合成的藥物SECTION 4 Antimitotic agents 抗有絲分裂的藥物抗有絲分裂的藥物SECTION 5 New targets for antineoplastic agents 抗腫瘤藥物的新靶點(diǎn)抗腫瘤藥物的新靶點(diǎn)SECTON 1 Intro

2、ductionneoplasm腫瘤腫瘤The medical term for cancer or tumor is neoplasm腫瘤腫瘤, 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 malignant neoplasm with potential danger.

3、sarcoma 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 mesodermal tissue is called sarcoma. . car

4、cinomaEctodermal cells form skin, its appendages, and nerve tissue. Endodermal cells form the intestinal system and its associated organsA cancer arises from ecto- or endodermal cells is called a carcinoma. BlastomaThe suffix-blastomais used to indicate certain types of tumors that have primitive ap

5、pearance resembling embryonic structures. Cancers of bloodA cancer of the blood involving abnormal increase of leukocytes is called leukemia.Cell growth cycles In a cells nucleus, DNA replication occurs during only one specific part of the cell cycle, called S for synthesis. Between division and S i

6、s 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. Although each of these four main periods of the cell cycle (G1, S, G2, M)

7、 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 dieSECTON 2 Agents directly acting on DNA作用于作用于DNA的藥物的藥物I Alkylating agents 烷化劑烷化劑II Platinum Complex (金屬鉑配合物金屬鉑配合物)III Bleomycin (博來霉

8、素類博來霉素類) IV 作用于作用于DNA拓?fù)洚悩?gòu)酶拓?fù)洚悩?gòu)酶(topoismerase)的藥物的藥物I Alkylating agentsAlkylating agents are reactive compounds that act on DNA, RNA, and certain enzymes. 1. Nitrogen mustards2. Aziridines3. Methanesulfonate esters and multiple alcohols 4. Nitrosoureas5. Triazemylimidazole6. Hydrazine derivativesI Al

9、kylating agents 烷化劑烷化劑1. Nitrogen mustards氮芥類氮芥類 載體部分載體部分 烷基化部分烷基化部分NCH2CH2ClCH2CH2ClRSCH2CH2ClCH2CH2ClNCH2CH2ClCH2CH2ClHMechanism of nitrogen mustardsNCH2CH2ClCH2CH2ClR N+CH2CH2CH2ClRH2C N+CH2CH2CH2XRH2CX-NCH2CH2XCH2CH2ClR-Cl-Cl-Y-NCH2CH2XCH2CH2YRNNNNNH2HadenineHNNNNOHH2NguanineHNNOHOHNNOHCH3ONNNH2

10、HOcytosineuracilthymine 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 cross-linking, which interferes with separation of the strands and prevents mi

11、tosis. 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 ultimately carcinogenic, effect on bone marrow stem cells, culminating in a fo

12、rm of acute myelogenous leukemia.HClNCH2CH2ClCH2CH2ClCH3HClNCH2CH2ClCH2CH2ClCH3OMechlorethamine Hydrochloride (鹽酸氮芥鹽酸氮芥) MechlorethaminoxideHydrochloride(鹽酸氧氮芥鹽酸氧氮芥)*Chlorambucil Chlorambucil is used chiefly in chronic lymphocytic leukemia, usually orally because of its favorable aqueous solubility

13、as the sodium salt and rapid conversion to the free drug. Side effects are anorexia厭食厭食, nausea, and vomiting.N(CH2CH2Cl)2(CH2)3HOOC*Melphalan It is effective in multiple myeloma(骨髓骨髓瘤瘤)and has had a role in the treatment of breast and ovarian cancers.*Formylmerphalan ()-N-Formyl-4-bis-(b-chloroethy

14、l)amino-phenylalanine國(guó)產(chǎn)降低毒性國(guó)產(chǎn)降低毒性N(CH2CH2Cl)2CH2CHHOOCNH2CH2NCHCOOHNHCHOClCH2CH2ClCH2CH2Synthetic route of nitrogen mustardsNRCH2CH2ClCH2CH2ClSOCl2NRCH2CH2OHCH2CH2OH*Cyclophosphamide (環(huán)磷酰胺環(huán)磷酰胺)N,N-Bis(2-chloroethyl)tetrahydro-2H-1,3,2-oxazaphosphorin-2-amine-2-oxide monohydrateH2OPNClCH2CH2ClCH2CH2O

15、NOHIfosfamide (異環(huán)磷酰胺異環(huán)磷酰胺) Trofosfamide (曲磷胺曲磷胺)PO(ClCH2CH2)2NCH2CH2ClNOPOClCH2CH2NHCH2CH2ClNO2. Aziridines 乙撐亞胺類乙撐亞胺類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)NNNNNNCH2H2CH2CH2CCH2CH2NNNNNNCH3H3CCH3CH3H3CH3Cp472Tepa *Thiotepa(替哌替哌) (塞替哌塞替哌) PSNNNPONNN*Mi

16、tomycin C (絲裂霉素絲裂霉素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烏拉坦烏拉坦,氨基甲酸乙氨基甲酸乙酯酯.OOH2NCH3NOCNH2NHOCH3OReaction scheme for bioreductive activation of mitomycin C and the sub

17、sequent interstrand cross-linking of DNA.DNA- CH3OH2H+e-, EnzymeHetcHO2+OOH2NCH3NNHDNAO2DNAOHOHH2NCH3NNHOHOHH2NCH3NOCNH2NHOOHOHH2NCH3NOCNH2NHOCH3OO-O-H2NCH3NOCNH2NHOCH3OOOH2NCH3NOCNH2NHOCH3O3. Methanesulfonate esters and multiple alcohols 甲磺酸酯及多元醇類甲磺酸酯及多元醇類*Busulfan (白消安，馬利蘭)雙功能的烷化劑，臨床對(duì)于慢性粒細(xì)胞白血病的療效顯

18、著SOCH3OO(CH2)4OSOOCH3Dibromomannitol Dibromodulcilol (二溴甘露醇二溴甘露醇) (DBD, 二溴衛(wèi)矛醇二溴衛(wèi)矛醇)Dianhydrogalactitol (DAG, 脫水衛(wèi)矛醇脫水衛(wèi)矛醇): R=HDiacetyl dianhydrogalactitol (DADAG, 脫水衛(wèi)矛醇雙乙?；锩撍l(wèi)矛醇雙乙酰化物): R=-COCH3H2CCOHCHCORHOROCH2CCCBrCH2HOHCHOH HOHCCH2BrOHHCCBrCH2HOHCOHHHOHCCH2BrHOH*Carmustine, BCNU卡莫司汀,卡氮芥CNHNCH2CH2

19、ClClH2CH2CNOON,N-Bis(2-chloroethyl)-N-nitrosourea4. Nitrosoureas亞硝基脲類亞硝基脲類* Synthetic route of Carmustine (BCNU,卡莫司汀卡莫司汀,卡氮芥卡氮芥)NCClCH2CH2NONHCH2CH2ClOHCOOHNaNO2DMFH2NCH2CH2OHNHOOCH2NH2NOHOCH2CH2NHCONHCH2CH2OHSOCl2HOCH2CH2NH2+CClCH2CH2NHClCH2CH2NHOLomustine (CCNU, 洛莫司汀洛莫司汀) : R=Semustine (Me-CCNU,司莫

20、司汀司莫司汀) : R=Nimustine (ACNU,鹽酸尼莫司汀鹽酸尼莫司汀) : R=Ranimustine (雷莫司汀雷莫司汀): R=ClCH2CH2NNOCNHROCH3CH2NNNH2CH3CH2OOHOHOHOCH3Decomposition of chloroethylnitrosoureas.ClCH2CH2NNOCNHROClCH2CH2NN OHCNRO+ClCH2CH2+N2+OH-carbamoylationalkylation氨甲酰化Streptozotocin (鏈左托星鏈左托星): R=CH3Chlorozotocin (DCNU,氯脲霉素氯脲霉素): R=C

21、H2CH2ClCH2OHOOHOHHNHCONROHNO5. Triazemylimidazole三氮烯咪唑類三氮烯咪唑類 *Dacarbazine (DTIC, 達(dá)卡巴嗪達(dá)卡巴嗪) 5-(3,3-dimethyl-1-triazemyl)-imidazole-4-carboxamide臨床用于黑色素病，何杰金氏病的治療臨床用于黑色素病，何杰金氏病的治療NNNNNCH3CH3CONH2HBioactivation of dacarbazine.NNNH2CONH2HNNNHNNCH3CONH2HNNNNNHCH3CONH2HNNNNNCH3CH3CONH2HNNNNNCH2OHCH3CONH2

22、H+HCHOCO2+OH-,NN+CH3orCH2N2N2+CH3+H+ 肝氧化酶系非酶水解6. Hydrazine derivatives肼類肼類*Procarbazine Hydrochloride (丙卡巴肼，甲基芐肼丙卡巴肼，甲基芐肼)N-isopropyl-(2-methyl-hydrazino-p-toluamide hydrochloride)CNHCHCH3NHNHCH2CH3CH3O. HClBioactivation of Procarbazine hydrochloride in vivo.烷基化烷化H2O. HClCNHCHCH3NHNHCH2CH3CH3OCNHCHN

23、CH2CH3CH3OCH3NCNHCHNCH2CH3CH3OCH3NOCNHCHNCH2CH3CH3OHOCH2NO-H2OCH3N+NH2OCNHCHN+CH2CH3CH3ONNADPH , O2NADP-NADP-,NADPH , O2H2OP-450P-450細(xì)胞色素細(xì)胞色素CNHCHNCHCH3CH3OCH3NOOHCNHCHNCH2CH3CH3OCH3NO肝微粒體肝微粒體烷化烷基化p479II Platinum Complex (金屬鉑配合物金屬鉑配合物) *Cisplatin (順鉑順鉑) Cisplatin is the most active single agent agai

24、nst nonseminomatous(非精原細(xì)胞瘤的非精原細(xì)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 squamous and transitional cell carcinomas, and treatment of small-cell l

25、ung cancer.PtH3NH3NClClIII Bleomycin (博來霉素類博來霉素類) Bleomycin is a group of glycopeptides, with antitumor activity, isolated from Streptomyces verticillus放線菌放線菌. The clinical prepration is a mixture of bleomycin A2, A2I, B1-4, etc, with A2 the predominant component. Bleomycin causes strand scission an

26、d 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 lacks bone marrow toxicity and immune suppression. It has modest activity in a va

27、riety of squamous cell cancer.Bleomycin A2: X= Bleomycin B2: X= Bleomycin A5: X=NNCH3H2NNHNHONHNH2NH2OOHHNH2HOCH3HHHOCH3HNHNHHOHOCH3HNSSNXOONHNHOHOHOHOOOHOHOHOOONH2OS+(CH3)2X-NHNHNNH2NHHHNNHNH2p482Antitumor mechanism of Bleomycin. p4843GCGAAATTTCGC5CGCTTTAAAGCGO2BLMFe(II)HNNOOCH3HCHOOCH2COOHPOOO-CG+

28、HNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGHOOHNNOOOOPOOO-CGCH3OPOO-OT3A3GCGOHOO-POO-OT3A3GCGOHCOCH3CGO-OOPOOOONHN+2. Agents acting on TopoII (作用于作用于Topo II 的抗腫瘤藥物的抗腫瘤藥物)嵌入型抗腫瘤藥物嵌入型抗腫瘤藥物L(fēng)-蘇氨酸蘇氨酸 D-纈氨酸纈氨酸 L-脯氨酸脯氨酸 N-甲基甘氨酸甲基甘氨酸 L-N-甲基纈氨酸甲基纈氨酸放線菌素放線菌素D p48

29、5(Actinomycin D, Dactinomycin)H3CCONOH3CCONH2ONHNHCHCHCOCOCHCHH3CH3COONHNHCHCHC3H7COCOC3H7NNCOCONNCH2CH3CH2COCONNCH3CHCHC3H7C3H7CH3CH3CCOO吩噁嗪環(huán) Actinomycin is the most active of a series of cyclic pentapeptides isolated from Streptomyces parvulus. The chemical structure of the antibiotics is composed

30、 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 between base pairs as in a sandwich, and perpendicular to the main axis of the helix, as are the base pairs. Because

31、 of its flat rigid aromatic structure, the oxazine噁嗪噁嗪portion of actinomycin can bind nonconvalently between two successive bases in DNA, elongating the DNA.p486Doxorubicin (Adriamycin，多柔比星，阿，多柔比星，阿霉素霉素)OOOOHOHCH2OHOOHOCH3OHNH2OCH3123456789101112131412345*Daunorubicin Epirubicin(Daunomycin，柔紅霉素，柔紅霉素

32、) (表柔比星，表阿霉素表柔比星，表阿霉素)OOOOHOHCH3OOHOCH3OHNH2OCH3OOOOHOHCH2OHOOHOCH3HONH2OCH3 Anthracyclines 蒽環(huán)類抗腫瘤抗生素蒽環(huán)類抗腫瘤抗生素represents a major class of antineoplastic drugs. Doxorubicin is probably the most important anticancer drug available because of its relatively broad spectrum of activity, and daunorubicin

33、is an important agent in the treatment of acute lymphocytic and myelocytic leukemia. Doxorubicin has a significant role in the treatment of solid tumors such as carcinoma of the breast, lung, thyroid, and ovary, as well as soft tissue sarcomas.Zorubicin 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

34、霉素) OCH3OOOHOHNCH3OHOOCH3ONH2HNHCC6H5OHOHOOOHOHOON(CH3)2OCH3COOCH3CH3OOHOOCH3O* Mitoxantrone (Novantrone，米托蒽醌，米托蒽醌) 1,4-dihydro-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.OHOHOO

35、NH(CH2)2NH(CH2)2OHNH(CH2)2NH(CH2)2OHHCNNHHNNHCNNHHNN SECTION 3 Agents interfering with DNA synthesisI Pyrimidine antagonists II Purines antagonistsIII Folic Acid AntagonistsI 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

36、)-pyrimidinedioneHNNOHFO Fluorouracil must be phosphorylated to the nucleotide to be active and, as such, inhibits thymidylate(胸苷酸胸苷酸)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 monop

37、hosphates 5-FUMP and 5-FdMP; the latter binds tightly to thymidylate synthetase and inhibits the eventual synthesis 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 tr

38、anscription.Antitumor Mechanism of Fluorouracil.HNNORFPdO+Nu-EnzHNNO-RFPdONu EnzNNNNNCOGluOHH2NHNNNNNCOGluOHH2NCH2HNOONuRPdFEnzHHHNNORCH3PdO+HH2NOHCOGluNNNNNHNu-Enz脫氧氟尿嘧啶核苷酸胸腺嘧啶合成酶+Hydrolysis of Fluorouracil .O-NNH2OSO3-OFHOH-O-HOHFOHNNOFOSO3-HHSO3-OH-或O-NNH2OHOFH-SO32-FHNNOHOSO3-HHNNOFOHKE+HNNOFOHII Purines antagonists (嘌呤拮抗物嘌呤拮抗物)*6-Mercaptopurine HypoxanthineNNNNSHHNNNNOHH 6-MP is inactive until metabolized to their respective monophosphate ribonucleoti