Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?
文献类型：期刊论文
| 作者 | Deng, Jing1; Feng, Enguang2; Ma, Sheng3; Zhang, Yan3; Liu, Xiaofeng1; Li, Honglin1; Huang, Huang1; Zhu, Jin1; Zhu, Weiliang2 ; Shen, Xu1,2
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2011-07-14 |
| 卷号 | 54期号:13页码:4508-4522 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm200161c |
| 文献子类 | Article |
| 英文摘要 | RhoA is a member of Rho GTPases, a subgroup of the Ras superfamily of small GTP-binding proteins. RhoA, as important regulator of diverse cellular signaling pathways, plays significant roles in cytoskeletal organization, transcription, and cell-cycle progression. The RhoA/ROCK inhibitors have emerged as a new promising treatment for cardiovascular diseases. However, to date, RhoA inhibitors are macromolecules, and to our knowledge, small molecular-based inhibitors have not been reported. In this study, a series of first-in-class small molecular RhoA inhibitors have been discovered by using structure-based virtual screening in conjunction with chemical synthesis and bioassay. Virtual screening of similar to 200,000 compounds, followed by SPR-based binding affinity assays resulted in three compounds with binding affinities to RhoA at the micromolar level (compounds 1-3). Compound 1 was selected for further structure modifications in considering binding activity and synthesis ease. Fourty-one new compounds (1, 12a-v, 13a-h, and 14a-j) were designed and synthesized accordingly. It was found that eight (12a, 12j, 14a, 14b, 14d, 14e, 14 g, and 14h) showed high RhoA inhibition activities with IC(50) values of 1.24 to 3.00 mu M. A pharmacological assay indicated that two compounds (14g and 14 h) demonstrated noticeable vasorelaxation effects against PE-induced contraction in thoracic aorta artery rings and served as good leads for developing more potent cardiovascular agents. |
| WOS关键词 | RIBOSYLATING C3 EXOENZYME ; SMOOTH-MUSCLE ; CLOSTRIDIUM-BOTULINUM ; KINASE INHIBITORS ; CRYSTAL-STRUCTURE ; PROTEINS ; CELLS ; DISCOVERY ; DOCKING ; GTPASES |
| 资助项目 | National Natural Science Foundation of China[90813005] ; National Natural Science Foundation of China[20902022] ; National S&T Major Project, China[2009ZX09501-001] ; National S&T Major Project, China[2011ZX09102-005-02] ; Natural Science Foundation of Jiangsu Province[BK2008172] ; 111 Project[B07023] ; Fundamental Research Funds for the Central Universities[00000000] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000292479600015 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278476]  |
| 专题 | 药物发现与设计中心 药物化学研究室 |
| 通讯作者 | Li, Honglin |
| 作者单位 | 1.E China Univ Sci & Technol, Sch Pharm, Shanghai 200237, Peoples R China; 2.Chinese Acad Sci, Shanghai Inst Mat Med, Drug Discovery & Design Ctr, Shanghai 201203, Peoples R China; 3.Soochow Univ, Affiliated Hosp 1, Dept Clin Pharmacol, Res Lab, Suzhou 215006, Peoples R China |
| 推荐引用方式 GB/T 7714 | Deng, Jing,Feng, Enguang,Ma, Sheng,et al. Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?[J]. JOURNAL OF MEDICINAL CHEMISTRY,2011,54(13):4508-4522. |
| APA | Deng, Jing.,Feng, Enguang.,Ma, Sheng.,Zhang, Yan.,Liu, Xiaofeng.,...&Li, Jian.(2011).Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?.JOURNAL OF MEDICINAL CHEMISTRY,54(13),4508-4522. |
| MLA | Deng, Jing,et al."Design and Synthesis of Small Molecule RhoA Inhibitors: A New Promising Therapy for Cardiovascular Diseases?".JOURNAL OF MEDICINAL CHEMISTRY 54.13(2011):4508-4522. |
入库方式： OAI收割
来源：上海药物研究所
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