计算机辅助设计新型人脂肪酸合酶抑制剂及其抗肿瘤活性  

Computer Aided Design of Novel Human Fatty Acid Synthase Inhibitors and Their Antitumor Activities

作　　者：刘诗雨[1] 米婷婷[2] 任建东[2] 范开华[2] 何菱[1] 

机构地区：[1]四川大学华西药学院,四川成都610041 [2]中国人民解放军成都军区总医院药剂科,四川成都610083

出　　处：《合成化学》2016年第12期1038-1042,共5页Chinese Journal of Synthetic Chemistry

基　　金：国家自然科学基金资助项目(21072131);四川省科技厅科技支撑计划资助项目(2015SZ0168)

摘　　要：以Orlistat为先导化合物,利用Auto Dock进行计算机模拟对接,在对接结果中选择能量较低的6个结构进行合成与抗肿瘤活性筛选。以orlistat为原料,经2步反应制得苄基(2S,3S,5S)-2-己基-3,5-二羟基十六酸酯(2);再经4步反应获得(3S,4S)-3-己基-4-[(S)-2-羟基十三烷基]氧杂环丁烷-2-酮(5);5在EDCI作用下与酸经缩合反应合成了4个计新型人脂肪酸合酶抑制剂(6a^6d),其中6b^6d为新化合物,其结构经1H NMR,13C NMR和HR-MS(ESI)表征。体外初步活性测试表明:(S)-1-[(1S,2S)-3-己基-4-氧代氧杂环丁烷-2-基]十三烷-2-烟酸酯(6a)对MDA-MB-231细胞有较好的抑制作用,其IC50为11.72μmol·m L^(-1),优于Orlistat(21.5μmol·m L^(-1))。With orlistat as the pilot, six compounds with low-energy structures were chosen by computer stimulation for further synthesis and a ntineoplastic activity screening using AutoDock. Benzyl （2S, 3S ,5S） -2-hexyl-3,5-dihydroxyhexadecanoate （2） was prepared by two steps of reaction from Orlistat. （3S,4S） -3-hexyl-4-[ （S） -2-hydroxytridecyl] oxetan-2-one （ 5 ） was prepared by four steps of reaction from 2. Human fatty acid synthase inhibitors（6a - 6d） were obtained from 5 by condensation reaction with corresponding acid in the presence of EDCI, Among them 6b - 6d were novel compounds. The structures were characterized by t H NMR, 13C NMR and HR-MS （ESI）. In vitro test results showed that（S） -1-[ （2S,3S） -3-hexyl4-oxooxetan-2-yl] tridecan-2-yl nicotinate（6a） exhibited better inhibito- ry activity against fatty acid synthase with IC50 of 11.72 μmol·mL-1, which is better than Orlistat （21.5 μmol · mL - 1 ）.

关 键 词：ORLISTAT 计算机辅助药物设计 抗肿瘤活性 合成 人脂肪酸合酶抑制剂 

分 类 号：O621.3[理学—有机化学]