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1、Chapter 13 Antineoplastic Agents,Malignant tumor is a serious threat to human health and the frequently-occurring diseases, the human death caused by malignant tumors is the second place among the death of all disease.,Therapy：,Surgical operation Radiation therapy Chemical treatment,Antineoplastic a
2、gents aim at anti-malignant tumor, also known as anti-cancer drugs.,Classification by mechanism,1. Alkylating agents 2. Antimetabolites 3. Drugs intefering with synthesis of protein of tumor cells,13.1 Biological alkylating agents,1.Nitrogen mustards 2.Ethylene imines 3.Sulfonates and halogenated po
3、lyols 4.Nitrosourea,Bioalkylating agents are cytotoxic drugs. In vivo, it is able to form a positive charged carbon-ion or other active electrophilic groups, and then the electrophilic ions combine covalently with electron rich groups (such as amino, sulfhydryl, hydroxyl, carboxyl, phosphate, etc.)
4、of the cells of biological macromolecules (DNA, RNA, enzymes), lead to the breaking of DNA molecule, at last result in the death of tumor. However, bioalkylating drugs also inhibit the normal cells with the property of rapid proliferation such as bone marrow cells, intestinal epithelial cells at sam
5、e time. So the bioalkylating agents have more serious side effects, such as nausea, vomiting, bone marrow suppression and hair loss. Clinical usually are carrying on combined use with other drugs.,Biological alkylating agents,General formula of nitrogen mustards,（1）Fraction of alkylation is anti-tum
6、or function group, existing as bis-chloro-ethylamine. （2）Fraction of carrier：可以改善药物药代动力学性质，选用不同载体，可提高选择性和抗肿瘤活性。依据载体化学结构，可分为脂肪氮芥、芳香氮芥、氨基酸氮芥、杂环氮芥和甾体氮芥。,13.1.1 Nitrogen mustards,Mechlorethamine hydrochloride,N-甲基-N-（2-氯乙基）-2-氯乙胺盐酸盐,N-methyl-N-(2-chloroethyl)-2-chloroethylamine hydrochloride,Clinical ap
7、plication: mainly treatment for lymphosarcoma and Hodgkins disease,Development: during the First World War, nitrogen mustard was used as a toxic gas, shortly after it was found the property of inhibiting bone marrow and lymphoid tissue of the victims. In 1942, Gilman from Yale University firstly use
8、d nitrogen mustard in the treatment of lymphoid neoplasms.,Different R：脂肪氮芥、芳香氮芥,Alkylation process:,脂肪氮芥的氮原子碱性比较强，烷基化历程是双分子亲核取代反应，活泼的乙撑亚胺离子极易与细胞成分的亲核中心起烷化作用，属强烷化剂。,It is usually used as injection drug of aqueous solution, which pH value maintained at 3.0 5.0.,Stability：,Chlormethine hydrochloride p
9、resented strong destruction to tumor cells, but with poor selectivity and large toxicity. Only Effective for lymphoma, so structural modification is necessary.,Nitromin: Reduced the possibility of formation of ethylene imine for the reduced electronic cloud on nitrogen. Nitromin is less toxicity, bu
10、t also the reduced anti-tumor activity.,N,C,H,3,C,l,C,l,O,2. Aromatic nitrogen mustards: The introduction of aromatic ring led to reduction of alkalescence by reason of conjugation, so mechanism was changed, no formation of cyclic ethylene imine ion but the formation of carbon cation intermediate.,C
11、yclophosphamide,P-N，N-双-（-氯乙基）-1-氧-3-氮-2-磷杂环己烷-P-氧化物一水合物。 With a broad spectrum of anti-tumor。,Physicochemical properties of cyclophosphamide,White crystal or crystalline powder (失去结晶水即液化) Soluable in water, unstable in aqueous solution and easily hydrolyze, easily decompose under heating condition.
12、 Cyclophosphamide is a prodrug.在肝脏被活化，经非酶促的-消除反应生成丙烯醛（膀胱毒性）、磷酰氮芥及去甲氮芥，三者都是较强的烷化剂。,Cyclophosphamide has a broad spectrum of anti-tumor, clinical for treatment of malignant lymphoma, acute lymphocytic leukemia, multiple myeloma, lung cancer etc.,Clinical application of cyclophosphamide,以二乙醇胺作为原料，用过量的三
13、氯氧磷同时进行氯代和磷酰化，制得氮芥磷酰二氯，再与3-氨基丙醇缩合。,Synthesis of cyclophosphamide,美法仑 Melphalan,氮芥类的烷化剂，结构包括氮芥和L-苯丙氨酸部分，氮芥部分在碱性水溶液中易水解，含有氨基酸结构，会发生茚三酮显色反应，且有氨基酸两性性质。,氮芥类药物是通过在体内转变成乙撑亚胺中间体发挥烷化剂作用，乙撑亚胺的磷酰胺衍生物，可提高抗肿瘤作用及减小毒性。 Tepa was clinical used for treatment of leukaemi。 Thiotepa changed into tepa in vivo. Clinical f
14、or the treatment of breast cancer, ovarian cancer, bladder cancer, and so on.,13.1.2 Ethylene imines,Tepa,Thiotepa,Sulfonates and halogenated polyols are non-nitrogen mustard alkylating agents。甲磺酸酯是较好的离去基团，生成碳正离子与生物大分子发生亲核取代反应进行烷基化。Busulfan,also known as Myleran, named as:4-Butanediol dimethyl sulfo
15、nate。Clinical for the treatment of chronic myeloid leukemia. 多元醇类药物主要是卤代多元醇，进入体内后会形成双环氧化物而产生烷化作用。二溴甘露醇(Dibromomannitol)、二溴卫矛醇(Dibromodulcilol)等。,13.1.3 Sulfonates and halogenated polyols,13.1.4 Nitrosoureas,N-亚硝基的存在使该氮原子与邻近羰基之间的键变得不稳定，在体内分解生成亲电性基团，破坏DNA的结构。 Nitrosoureas are highly lipophilic, easily
16、 pass through the blood-brain barrier for treatment of brain tumors, central nervous system tumors and malignant lymphoma, but with side effects of delayed bone marrow suppression. Clinical used drugs includes Carmustine（卡莫司汀）， Lomostine (洛莫司汀)， Semustine(司莫司汀)， Nimustine(尼莫司汀) and so on.,卡莫司汀Carmustine,N，N-双（-氯乙基)-N-亚硝基脲，又名卡氮芥 N, N-bis-(-chloroethyl)-N-nitrosourea,Carmustine is highly lipophilic, easily pass through the blood-brain barrier for
