新型苯并硫氮杂酮类非ATP竞争GSK-3β抑制剂的设计合成和活性.PDF

·生物化学· 新型苯并硫氮杂酮类非ATP 竞争GSK-3β抑制剂的设计、合成和活 性评价 黄朝辉1 2 3 3* 3 ，胡海荣 ，雷贾毅 ，楚勇 ，叶德泳 (1.浙江省宁波市药品检验所，浙江 宁波 315048 ；2.复旦大学生命科学学院， 上海 200433 ；3.复旦大学药学院药化教研室，上海 200032) 摘要：目的 寻找新型的非ATP 竞争糖原合成酶激酶-3β(GSK-3β)抑制剂。方法 针对 GSK-3β 的非ATP 结合的底物作 用位点为靶点，采用Autodock 程序对类药性小分子库Maybridge 进行虚拟筛选寻找新型GSK-3β抑制剂。采用克脑文格 尔反应，环合及 N-烷基化反应制备目标化合物。采用体外酶抑制活性测试目标化合物的活性。结果 化合物 2-(2-呋喃 基)-5-苄基-2,3-二氢苯并[b][1,4]硫氮杂-4(5H)-酮对GSK-3β具有中等抑制活性(IC50 47.69±2.38 µmol·L1) 。结论 活性化 合物的结构与目前报道的其他GSK-3β抑制剂不同，可望作为新的先导化合物，值得进一步研究。 关键词：糖原合成酶激酶-3β；虚拟筛选；抑制剂；合成 中图分类号：R914.2 文献标志码：B 文章编号：1007-7693(2012)11-0988-05 Design, Synthesis and in Vitro Test of Novel Non-ATP Competitive Glycogen Synthase Kinase-3β(GSK-3β) Inhibitors 1 2 3 3* 3 HUANG Zhaohui , HU Hairong , LEI Jiayi , CHU Yong , YE Deyong (1.Ningbo Institute for Drug Control, Ningbo 315048, China; 2.School of Life Sciences, Fudan University, Shanghai 200433, China; 3.School of Pharmacy, Fudan University, Shanghai 200032, China) ABSTRACT: OBJECTIVE To discover novel non-ATP competitive glycogen synthase kinase-3β(GSK-3β) inhibitors. METHODS A virtual screening was conducted by Autodock program, which docked the small drug-like molecules of Maybridge library at the non-ATP binding site of GSK-3β. The target compounds had been designed based on the virtual screening result and successfully synthesized through Knoevenagel reaction, cyclization and N-alkylation. The inhibition to GSK-3β was tested by in vitro enzamic test. RESULTS 5-benzyl-2-(furan-2-yl)-2,3-dihydrobenzo[b][1,4] thiazepin-4(5H)-one showed moderate inhibition to GSK-3β in vitro (IC50 47.69±2.38 µmol·L1). CONCLUSION The discovered new active compound is structurally different to other inhibitors of GSK-3β and worthy of further study as a novel le