Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors
文献类型：期刊论文
| 作者 | Chai Qian1; Shen Qiang2; Ma Lan-Ping1 ; Wang Xin1; Meng Tao1; Li Jing-Ya2; Li Jia2; Shen Jing-Kang1
|
| 刊名 | CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE
 |
| 出版日期 | 2011-02-10 |
| 卷号 | 32期号:2页码:306-315 |
| 关键词 | Protein tyrosine phosphatase High-throughput screening Tetrahydro-3H-cyclopenta[c]quinoline-4-carboxylic acid Inhibitor |
| ISSN号 | 0251-0790 |
| 文献子类 | Article |
| 英文摘要 | The protein tyrosine phosphatases (PTPs) constitute a family of closely related key regulatory enzymes that dephosphorylate phosphotyrosine residues in their protein substrates. Malfunctions in PTP activity are linked to various diseases, ranging from cancer to neurological disorders and diabetes. As part of a project aimed at identifying small molecular inhibitors based on PTPs family, focusing on diabetes mellitus, tumorigenesis, and infection, we performed the high-throughput screening (HTS) of a library of 48000 synthetic compounds for six representative PTPs, including PTP1B, SHP-1, SHP-2, PRL-3, CDC25B and LAR, and 3a,4,5,9b-tetrahydro-3H-cyclopenta[c]quinoline analogues were identified as PTPs inhibitors. Keeping the core template complete, we began the modification of benzene ring, intending to find out the best modifying position in benzene ring and the proper amount of substitutions on it. Consequently, thirty-four compounds were designed and synthesized, and careful structure-activity relationship(SAR) study with respect to PTP1B, SHP-1, SHP-2, PRL-3, CDC25B and LAR was carried out. Finally, it was found that the compounds bearing a bulky substituent at 8-position of the cyclopentaquinoline acid turned out to be PTP1B inhibitors with good potency and selectivity against other assayed PTPs. The most potent PTP1B inhibitor in this series, compounds 31 and 35, show good activity(IC50 = 0.4 and 0.6 mu mol/L, respectively) and excellent selectivity for PTP1B over SHP-1, SHP-2, PRL-3 and LAR, and 30-fold selectivity over CDC25B. Due to time limit, the modification of core template is not sufficient enough, and it would be the direction of our further work to discover more potent core structures. |
| WOS关键词 | PROTEIN-TYROSINE PHOSPHATASES ; SMALL-MOLECULE INHIBITORS ; SPECIFICITY ; 1B ; TARGETS |
| WOS研究方向 | Chemistry |
| 语种 | 中文 |
| CSCD记录号 | CSCD:4132690 |
| WOS记录号 | WOS:000287826200021 |
| 出版者 | HIGHER EDUCATION PRESS |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278605]  |
| 专题 | 药物化学研究室 中科院受体结构与功能重点实验室 新药研究国家重点实验室 |
| 通讯作者 | Ma Lan-Ping |
| 作者单位 | 1.Chinese Acad Sci, State Key Lab Drug Res, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China |
| 推荐引用方式 GB/T 7714 | Chai Qian,Shen Qiang,Ma Lan-Ping,et al. Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors[J]. CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE,2011,32(2):306-315. |
| APA | Chai Qian.,Shen Qiang.,Ma Lan-Ping.,Wang Xin.,Meng Tao.,...&Shen Jing-Kang.(2011).Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors.CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE,32(2),306-315. |
| MLA | Chai Qian,et al."Discovery and Structure-activity Relationships of Tetrahydro-3H-cyclopenta[c]quinolines Scaffold-based Potential PTP1B Inhibitors".CHEMICAL JOURNAL OF CHINESE UNIVERSITIES-CHINESE 32.2(2011):306-315. |
入库方式： OAI收割
来源：上海药物研究所
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