苯并噻嗪酮类GSK-3β非ATP竞争型抑制剂的设计、合成与生物活性评价  

Design,synthesis and biological evaluation of benzothiazinones as novel non-ATP competitive inhibitors of glycogen synthesis kinase 3β(GSK-3β)

作　　者：鹿文博[1] 张鹏[1] 黄科[1] 楚勇[1,2] 叶德泳[1] 

机构地区：[1]复旦大学药学院药物化学教研室,上海201203 [2]中国科学院上海药物研究所新药研究国家重点实验室,上海201203

出　　处：《中国药物化学杂志》2013年第6期444-452,共9页Chinese Journal of Medicinal Chemistry

基　　金：国家自然科学基金面上项目(81373275);上海市自然科学基金项目(10ZR1401800);中国科学院上海药物研究所新药研究国家重点实验室开放基金项目(SIMM1302KF-11)

摘　　要：目的设计合成新型的苯并噻嗪酮类化合物,并研究其对GSK-3β酶的抑制活性和动力学作用模式,以期发现新型的GSK-3β非ATP竞争型抑制剂。方法采用分子杂交方法设计了一系列苯并噻嗪酮类化合物。以苯并噻嗪酮(1)为起始原料,经过一步取代反应,在N原子上引入不同取代基得到中间体2a^2d,然后在羰基α碳上引入酰基得到中间体3a^3d及目标化合物3e,再通过肼解反应得到相应的酰肼4a^4d,最后在缩合剂作用下酰肼与不同的有机酸缩合得到目标化合物5a^5u。目标化合物以化学发光法测试其GSK-3β体外酶抑制活性,并通过动力学实验确定了其酶抑制作用模式。结果与结论合成的22个目标化合物均为新化合物,其结构均经过核磁和质谱确证。其中6个化合物对GSK-3β表现出一定的抑制活性(IC50<30μmol·L-1),活性最好的化合物5h与目前文献报道的GSK-3β非ATP竞争型抑制剂活性相当。酶动力学实验证实5h为非ATP竞争型和非底物竞争型抑制剂。本文还初步总结了该类化合物的构效关系。The study of non-ATP competitive inhibitors of GSK-3β had aroused more and more concern, es- pecially in the area of Alzheimer＇s disease. Compared with ATP competitive inhibitors ,non-ATP competitive inhibitors had higher selectivity. Unfortunately, the reported non-ATP competitive inhibitors were usually with poor inhibitory activities（IC50 = 1 -100 μmol.L-1） so far. So it is necessary to find more non-ATP competitive inhibitors. The benzothiazinone compounds were designed based on both the core structure of leading compound HZjb（IC50 = 100 μmol L-1） and the side chain of reported novel compound VP 0. 7 （ IC50 = 3 μmol. L -1 ） guided by the theory of molecular hybridization. Totally twenty two target compounds were synthesized and the structures were confirmed by MS and 1H-NMR. The inhibitory activities were car- ded out by chemluminescence with TDZD-8 as the reference compound. Among them, IC50 values of six compounds were below the level of 30 μmol. L-1 and the best one 5h（ IC50 -- 11.9 μmol L-1 ） was equiva- lently active to the reported non-ATP competitive inhibitors. The structure-activity relationships analysis of the benzothiazinones showed that both the length and the flexibility of side chain were of essential important to the activity. Furthermore, the compound 5h was confirmed by dynamic experiments to be both non-ATP competitive and non-substrate competitive. That kind of compounds was proposed to be located in the specific allosteric site of GSK-3β.

关 键 词：合成 苯并噻嗪酮 GSK-3Β 非ATP竞争型抑制剂 构效关系 

分 类 号：R914[医药卫生—药物化学]