3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x(L) and Mcl-1 | |
Song, Ting1; Li, Xiangqian1; Chang, Xilong2; Liang, Xiaomeng1; Zhao, Yan3; Wu, Guiye1; Xie, Shenghui1; Su, Pengchen1; Wu, Zhiyong1; Feng, Yingang4; Zhang, Zhichao1 | |
2013 | |
发表期刊 | BIOORGANIC & MEDICINAL CHEMISTRY |
卷号 | 21期号:1页码:11-20 |
摘要 | Based on the binding mode of our previously discovered dual inhibitor of Bcl-2 and Mcl-1, 3-thiomorpholin-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-carbonitrile (3, S1), a library of 9-substituted 3 derivatives was synthesized to further probe the p4 pocket of the two targets. By NMR, structure-activity relationship study, and site-directed mutation, compound 6d (3-(4-aminophenylthio)-8-oxo-8H-acenaphtho[1,2-b]pyrrole-9-3-phenyl)propylamine) was identified to span p2-p4 pockets of Mcl-1, Bcl-2 and Bcl-x(L), and then exhibited 9- to 35-fold better affinity to the three targets than 3 (IC50 = 10, 20 and 18 nM, respectively), which led to greater activity in induction of apoptosis in multiple cancer cell lines. Different contribution of p4 pocket to binding Bcl-2 and Mcl-1 was also investigated by plotting the potency and the HAC of the derivatives. (C) 2012 Elsevier Ltd. All rights reserved. |
文章类型 | Article |
关键词 | Pan-bcl-2 Inhibitor Bcl-2 Mcl-1 P4 Pocket Apoptosis |
WOS标题词 | Science & Technology ; Life Sciences & Biomedicine ; Physical Sciences |
DOI | 10.1016/j.bmc.2012.11.008 |
关键词[WOS] | SMALL-MOLECULE INHIBITORS ; CANCER-THERAPY ; IN-VIVO ; APOPTOSIS ; DEGRADATION ; MECHANISMS ; PROTEINS ; ABT-737 ; DESIGN ; POTENT |
收录类别 | SCI |
语种 | 英语 |
WOS研究方向 | Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry |
WOS类目 | Biochemistry & Molecular Biology ; Chemistry, Medicinal ; Chemistry, Organic |
WOS记录号 | WOS:000312275500001 |
引用统计 | |
文献类型 | 期刊论文 |
条目标识符 | http://ir.qibebt.ac.cn/handle/337004/6025 |
专题 | 代谢物组学研究组 |
作者单位 | 1.Dalian Univ Technol, Sch Chem, State Key Lab Fine Chem, Dalian 116012, Peoples R China 2.Peking Univ, State Key Lab Nat & Biomimet Drugs, Beijing 100191, Peoples R China 3.Dalian Univ Technol, Sch Life Sci & Technol, Dalian 116024, Peoples R China 4.Chinese Acad Sci, Qingdao Inst BioEnergy & Bioproc Technol, Qingdao 266101, Peoples R China |
推荐引用方式 GB/T 7714 | Song, Ting,Li, Xiangqian,Chang, Xilong,et al. 3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x(L) and Mcl-1[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2013,21(1):11-20. |
APA | Song, Ting.,Li, Xiangqian.,Chang, Xilong.,Liang, Xiaomeng.,Zhao, Yan.,...&Zhang, Zhichao.(2013).3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x(L) and Mcl-1.BIOORGANIC & MEDICINAL CHEMISTRY,21(1),11-20. |
MLA | Song, Ting,et al."3-Thiomorpholin-8-oxo-8H-acenaphtho [1,2-b] pyrrole-9-carbonitrile (S1) derivatives as pan-Bcl-2-inhibitors of Bcl-2, Bcl-x(L) and Mcl-1".BIOORGANIC & MEDICINAL CHEMISTRY 21.1(2013):11-20. |
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