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Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin

文献类型：期刊论文

作者Liu, Xiaohua3; Zhang, Yu2; Huang, Wenjing2; Luo, Jia2; Li, Yang3; Tan, Wenfu2; Zhang, Ao1,3,4
刊名EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY
出版日期2018-11-05
卷号159页码:149-165
关键词Apoptosis Artemisinin Bcl-2 Venetoclax Selectivity
ISSN号0223-5234
DOI10.1016/j.ejmech.2018.09.059
文献子类Article
英文摘要By taking advantage of the apoptosis-inducing capacity of artemisinin derivatives, we developed several series of compounds by merging the basic structural elements of the natural product artemisinin into the P2 interaction pocket of the clinically prescribed Bcl-2 inhibitor venetoclax. Most of the new compounds displayed improved biochemical potency against Bcl-2 and high selectivity over Bcl-xL. Specifically, compounds 27c and 34c were found to be the most potent with IC50 values less than 2.0 nM. Unfortunately, these compounds only showed moderate antiproliferative effects against Bcl-2 dependent cells. Though further structural optimization is needed to improve the cellular absorptive permeability, the current approach represents an alternative strategy to develop novel Bcl-2 inhibitors with greater selectivity over Bcl-xL, which is related to the off-target adverse effects of venetoclax. (C) 2018 Elsevier Masson SAS. All rights reserved.
WOS关键词ACUTE LYMPHOBLASTIC-LEUKEMIA ; PHARMACOLOGICAL EVALUATION ; ANTICANCER AGENTS ; CANCER-CELLS ; DERIVATIVES ; APOPTOSIS ; DISCOVERY ; PROTEINS ; DIMERS ; DIHYDROARTEMISININ
资助项目National Science Foundation of China[81773565] ; National Science Foundation of China[81773767] ; National Science Foundation of China[81430080] ; National Science Foundation of China[81573452] ; National Program on Key Basic Research Project of China[2015CB910603-004] ; International Cooperative Program of the Chinese Academy of Sciences[GJHZ1622] ; Key Program of the Frontier Science of the Chinese Academy of Sciences[160621] ; Shanghai Commission of Science and Technology[16XD1404600] ; Shanghai Commission of Science and Technology[14431900400] ; Shanghai Commission of Science and Technology[16140902500]
WOS研究方向Pharmacology & Pharmacy
语种英语
WOS记录号WOS:000449237100012
出版者ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER
源URL[http://119.78.100.183/handle/2S10ELR8/279498]  
专题药理学第一研究室
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
药物化学研究室
通讯作者Tan, Wenfu; Zhang, Ao
作者单位1.ShanghaiTech Univ, Sch Life Sci & Technol, Shanghai 201210, Peoples R China;
2.Fudan Univ, Sch Pharm, Dept Pharmacol, Shanghai 201203, Peoples R China;
3.Chinese Acad Sci, SIMM, State Key Lab Drug Res, Key Lab Receptor Res, Shanghai 201203, Peoples R China;
4.Univ Chinese Acad Sci, Beijing 100049, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xiaohua,Zhang, Yu,Huang, Wenjing,et al. Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin[J]. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,2018,159:149-165.
APA Liu, Xiaohua.,Zhang, Yu.,Huang, Wenjing.,Luo, Jia.,Li, Yang.,...&Zhang, Ao.(2018).Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin.EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY,159,149-165.
MLA Liu, Xiaohua,et al."Development of high potent and selective Bcl-2 inhibitors bearing the structural elements of natural product artemisinin".EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY 159(2018):149-165.

入库方式： OAI收割

来源：上海药物研究所

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