N^5-甲基四氢叶酸类似物的合成及其蛋氨酸合成酶抑制活性研究  

Synthesis and activity of inhibiting methionine synthase of N^5-methyltetrahydrofolate analogues

作　　者：杜义青 袁蒙蒙[1] 王锰[1] 刘俊义[1,2] 张志丽[1] 

机构地区：[1]北京大学药学院化学生物学系,北京100191 [2]北京大学天然药物及仿生药物国家重点实验室,北京100191

出　　处：《中国药物化学杂志》2015年第6期415-423,共9页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金项目(21172014)

摘　　要：目的在蛋氨酸合成酶抑制剂先导化合物的基础上设计合成4-氨基-8,10-二去氮杂-N^5-取代四氢叶酸类似物和4-氨基-8-去氮杂-N^5,N10-二取代四氢叶酸类似物,并对其蛋氨酸合成酶(MS)抑制活性进行评价,以考察N^5位和N10位酰基取代基对活性的影响,寻找新的活性更高的蛋氨酸合成酶抑制剂。方法以2,4-二氨基-6-溴甲基吡啶并[3,2-d]嘧啶为原料,经Wittig反应、还原反应、酰胺化及水解反应合成目标化合物;采用分光光度法对目标化合物的蛋氨酸合成酶抑制活性进行考察。结果与结论合成了10个未见文献报道的目标化合物,其结构均经~1H-NMR、MS谱确证。生物活性结果表明,目标化合物Ⅰc和Ⅱa对蛋氨酸合成酶的抑制活性优于先导化合物7a。Cobalamin-dependent methionine synthase catalyzes the transfer of methyl group from N^5-methyl- tetrahydrofolate to homocysteine to produce tetrahydrofolate and methionine. Tetrahydrofolate will participate in the synthesis of purine and pyrimidine through the folic acid metabolism which is a crucial step in de novo biosynthesis of DNA. Methionine synthase is not only related to DNA biosynthesis, but also involved in the cancer cell cycle and apoptosis. So methionine synthase is an excellent target for anticancer drug research. In this study, a series of new compounds were designed and synthesized as tetrahydrofolate analogues. The structures of ten new target compounds（ Ia - Ie and Ha - lie） were characterized by 1H-NMR and MS. The activity results showed that compounds Ic and Ha exhibited good inhibitory effect toward methionine synthase, with ICs0 values of （ 3.0 ± 0. 67 ） μmol· L ^-1 and （0. 9 ±0.67 ） μmol· L^ - 1.

关 键 词：蛋氨酸合成酶 四氢叶酸类似物 抑制剂 抗肿瘤 

分 类 号：R914[医药卫生—药物化学]