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Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors

文献类型：期刊论文

作者Liu, Xiaoqi1; Hu, Yuanyuan1; Gao, Anhui2; Xu, Meng1; Gao, Lixin2; Xu, Lei2; Zhou, Yubo2; Gao, Jianrong1; Ye, Qing1; Li, Jia2
刊名BIOORGANIC & MEDICINAL CHEMISTRY
出版日期2019-02-15
卷号27期号:4页码:589-603
关键词3-Aryl-4-indolyl-maleimides IDH1/R132H inhibitors Tumor 2-HG Synthesis
ISSN号0968-0896
DOI10.1016/j.bmc.2018.12.029
通讯作者Ye, Qing(yeqing1975@zjut.edu.cn) ; Li, Jia(jli@simm.ac.cn)
英文摘要A series of 3-aryl-4-indolylmaleimide IDH1/R132H inhibitors with a novel structure was obtained by high-throughput screening and structure-based optimization. Most compounds such as 7a, 7d, 7h, 7i, 7k and 7o showed high inhibitory effects on IDH1/R132H and were highly selective against IDH1/WT, IDH2/WT, GDH, GK, and FBP. Evaluation of the biological activities and function at cellular level showed that compounds 7h, 7i and 7k could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Additionally, 7h could reversed the differentiation block of the myeloid leukemic cell line, TF-1, caused by the overexpression of IDH1/R132H. We also explore the structure-activity relationship based on the experimental data, with an attempt to pave the way for future studies.
WOS关键词SELECTIVE-INHIBITION ; IDH2 MUTATIONS ; LEUKEMIA ; 2-HYDROXYGLUTARATE ; LEUKEMOGENESIS ; DISCOVERY ; CANCERS
资助项目Natural Science Foundation of Zhejiang[LY18H300009] ; Postdoctoral Science Foundation of China[2014M550256] ; State Key Laboratory of Drug Research[SIMM1601KF-04] ; National Natural Science Foundation of China[81501310] ; Personalized Medicines-Molecular Signature-based Drug Discovery and Development, Strategic Priority Research Program of the Chinese Academy of Sciences[XDA12020328]
WOS研究方向Biochemistry & Molecular Biology ; Pharmacology & Pharmacy ; Chemistry
语种英语
WOS记录号WOS:000456835900002
出版者PERGAMON-ELSEVIER SCIENCE LTD
源URL[http://119.78.100.183/handle/2S10ELR8/290739]  
专题新药研究国家重点实验室
通讯作者Ye, Qing; Li, Jia
作者单位1.Zhejiang Univ Technol, State Key Lab Breeding Base Green Chem Synth Tech, Hangzhou 310032, Zhejiang, Peoples R China
2.Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Natl Ctr Drug Screening, Shanghai 201203, Peoples R China
推荐引用方式
GB/T 7714		 Liu, Xiaoqi,Hu, Yuanyuan,Gao, Anhui,et al. Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors[J]. BIOORGANIC & MEDICINAL CHEMISTRY,2019,27(4):589-603.
APA Liu, Xiaoqi.,Hu, Yuanyuan.,Gao, Anhui.,Xu, Meng.,Gao, Lixin.,...&Li, Jia.(2019).Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors.BIOORGANIC & MEDICINAL CHEMISTRY,27(4),589-603.
MLA Liu, Xiaoqi,et al."Synthesis and biological evaluation of 3-aryl-4-indolyl-maleimides as potent mutant isocitrate dehydrogenase-1 inhibitors".BIOORGANIC & MEDICINAL CHEMISTRY 27.4(2019):589-603.

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来源：上海药物研究所

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