Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-x(L) Inhibitors
文献类型：期刊论文
| 作者 | Feng, Yu1; Ding, Xiao4; Chen, Tao2; Chen, Lili1 ; Liu, Fang3; Jia, Xu1; Luo, Xiaomin4; Shen, Xu1; Chen, Kaixian4; Jiang, Hualiang4
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| 刊名 | JOURNAL OF MEDICINAL CHEMISTRY
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| 出版日期 | 2010-05-13 |
| 卷号 | 53期号:9页码:3465-3479 |
| ISSN号 | 0022-2623 |
| DOI | 10.1021/jm901004c |
| 文献子类 | Article |
| 英文摘要 | Development of inhibitors to antagonize the activities of antiapoptotic Bcl-2 family proteins is of particular interest in cancer chemotherapy. We discovered a quinazoline-2(1H)-thione derivative (DCBL55) as a new Bcl-x(L), Bcl-2, and Mcl-1 inhibitor by virtual database screening. We systematically modified the structure of compound 1 by chemical synthesis. The interactions of the compounds with Bcl-x(L), were predicted by molecular modeling simulations, which were confirmed by structure activity relationship analysis and protein mutation studies. Three locations at the hydrophobic groove of Bcl-x(L), referred to as P2, P4, and P5, were found to contribute to the ligand interactions. Although the compounds induced mitochondrial potential reduction, caspase activation, and ROS generation, the cytotoxicities and the ultrastructural changes of outer mitochondrial membrane suggested that the compounds may target additional proteins outside the Bcl-2 family. Altogether, the present study provides new lead compounds and critical structural information for further development of more potent and specific inhibitors of antiapoptotic Bcl-2 family proteins. |
| WOS关键词 | SMALL-MOLECULE INHIBITOR ; BCL-2 FAMILY PROTEINS ; HEMATOLOGIC MALIGNANCIES ; BCL-2-FAMILY PROTEINS ; CELL LINES ; APOPTOSIS ; LYMPHOMA ; LEUKEMIA ; CANCER ; EXPRESSION |
| 资助项目 | CAS[00000000] ; National Natural Science Foundation of China[20721003] ; National Natural Science Foundation of China[30870513] ; 863 Hi-Tech Program of China[2006AA020602] ; 863 Hi-Tech Program of China[2006AA020402] ; NSFC[20721003] ; Ministry of Science and Technology of China[2007CB947100] ; National Science and Technology[2009ZX09301-001] ; National Science and Technology[2009ZX09501-001] ; National Science and Technology[2009ZX09501-010] |
| WOS研究方向 | Pharmacology & Pharmacy |
| 语种 | 英语 |
| WOS记录号 | WOS:000277352800004 |
| 出版者 | AMER CHEMICAL SOC |
| 源URL | [http://119.78.100.183/handle/2S10ELR8/278898]  |
| 专题 | 药物化学研究室 药物发现与设计中心 药理学第三研究室 |
| 通讯作者 | Wang, Hui |
| 作者单位 | 1.Chinese Acad Sci, Dept Mol Pharmacol, Shanghai 201203, Peoples R China; 2.Chinese Acad Sci, Inst Nutr Sci, Shanghai Inst Biol Sci, Grad Sch, Shanghai 200031, Peoples R China; 3.Shenyang Pharmaceut Univ, Sch Pharmaceut Engn, Shenyang 110016, Liaoning, Peoples R China 4.Chinese Acad Sci, Ctr Drug Design & Discovery, Shanghai Inst Mat Med, Shanghai 201203, Peoples R China; |
| 推荐引用方式 GB/T 7714 | Feng, Yu,Ding, Xiao,Chen, Tao,et al. Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-x(L) Inhibitors[J]. JOURNAL OF MEDICINAL CHEMISTRY,2010,53(9):3465-3479. |
| APA | Feng, Yu.,Ding, Xiao.,Chen, Tao.,Chen, Lili.,Liu, Fang.,...&Liu, Dongxiang.(2010).Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-x(L) Inhibitors.JOURNAL OF MEDICINAL CHEMISTRY,53(9),3465-3479. |
| MLA | Feng, Yu,et al."Design, Synthesis, and Interaction Study of Quinazoline-2(1H)-thione Derivatives as Novel Potential Bcl-x(L) Inhibitors".JOURNAL OF MEDICINAL CHEMISTRY 53.9(2010):3465-3479. |
入库方式： OAI收割
来源：上海药物研究所
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