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根据生物电子等排原理对叶酸结构中蝶呤环进行改造;将4-位羰基改变为氨基;同时N_(10)上的氢以甲基取代,得甲氨蝶呤(MTX),是最早应用于临床的叶酸拮抗剂类抗肿瘤药物。在研究氨基蝶呤环与DHFR的结合作用时,发现增加N_1上的碱性,氨基与氮原子和DHFR形成氢键是非常要的;经X-衍射证实,蝶呤环4-位羟基被氨基取代后可使整个分子与DHFR的结合能力增强,因此,确定了蝶呤环部分2,4-二氨基是与DHFR活性中心结合的基本结构。N_5、N_8上
According to the principle of bioischelelectrophoresis, the folate ring in the folic acid structure was modified; the carbonyl group at 4-position was changed to amino group; and the hydrogen at N 10 was substituted with methyl group to obtain methotrexate (MTX) In clinical folic acid antagonist antineoplastic drugs. In the study of aminopterin ring and DHFR binding, it was found to increase the basic N_1, amino and nitrogen atoms and DHFR hydrogen bond formation is essential; confirmed by X-ray, the pteridine ring hydroxyl 4 was amino After substitution, the binding ability of the whole molecule to DHFR was enhanced. Therefore, it was confirmed that the 2,4-diamino group of the pteridine ring was the basic structure binding to the DHFR active center. N_5, N_8 on