Design,synthesis and biological evaluation of benzothiazinones as novel non-ATP competitive inhibitors of glycogen synthesis kinase 3beta (GSK-3beta)
文献类型：期刊论文
| 作者 | Lu Wenbo1; Zhang Peng1; Huang Ke1; Chu Yong2; Ye Deyong1 |
| 刊名 | Chinese Journal of Medicinal Chemistry
 |
| 出版日期 | 2013 |
| 卷号 | 23期号:6页码:444-452 |
| 关键词 | GSK-3beta synthesis benzothiazinones glycogen synthesis kinase 3beta non-ATP competitive inhibitor structure-activity relationships |
| ISSN号 | 1005-0108 |
| 其他题名 | 苯并噻嗪酮类GSK-3beta非ATP竞争型抑制剂的设计、合成与生物活性评价 |
| 文献子类 | Article |
| 英文摘要 | The study of non-ATP competitive inhibitors of GSK-3beta had aroused more and more concern,especially 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 (IC_(50) = 1 - 100 mumol ? 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(IC_(50) = 100 mumol ? L~(-1)) and the side chain of reported novel compound VP 0. 7 (IC_(50) =3 mumol ? 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 carried out by chemluminescence with TDZD-8 as the reference compound. Among them, IC_(50) values of six compounds were below the level of 30 mumol ? L~(-1) and the best one 5h(IC_(50) = 11. 9 mumol ? L~(-1)) was equiva-ently 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-3beta. |
| 资助项目 | 国家自然科学基金面上项目[00000000] ; 上海市自然科学基金项目[00000000] ; 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[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy (provided by Clarivate Analytics) |
| 语种 | 中文 |
| CSCD记录号 | CSCD:5016096 |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/269360]  |
| 专题 | 中国科学院上海药物研究所 |
| 作者单位 | 1.Department of Medicinal Chemistry, School of Pharmacy, Fudan University, Shanghai 201203, China.; 2.Department of Medicinal Chemistry, School of Pharmacy, Fudan University; 3.Shanghai Institute of Materia Medica, Shanghai 201203, China. |
| 推荐引用方式 GB/T 7714 | Lu Wenbo,Zhang Peng,Huang Ke,et al. Design,synthesis and biological evaluation of benzothiazinones as novel non-ATP competitive inhibitors of glycogen synthesis kinase 3beta (GSK-3beta)[J]. Chinese Journal of Medicinal Chemistry,2013,23(6):444-452. |
| APA | Lu Wenbo,Zhang Peng,Huang Ke,Chu Yong,&Ye Deyong.(2013).Design,synthesis and biological evaluation of benzothiazinones as novel non-ATP competitive inhibitors of glycogen synthesis kinase 3beta (GSK-3beta).Chinese Journal of Medicinal Chemistry,23(6),444-452. |
| MLA | Lu Wenbo,et al."Design,synthesis and biological evaluation of benzothiazinones as novel non-ATP competitive inhibitors of glycogen synthesis kinase 3beta (GSK-3beta)".Chinese Journal of Medicinal Chemistry 23.6(2013):444-452. |
入库方式： OAI收割
来源：上海药物研究所
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