3-(7-Azaindolyl)-4-indolylmaleimides as a novel class of mutant isocitrate dehydrogenase-1 inhibitors: Design, synthesis, and biological evaluation

被引：8

作者：

Hu, Yuanyuan ^{[1
]}

Gao, Anhui ^{[2
]}

Liao, Honghui ^{[3
]}

Zhang, Mengmeng ^{[2
]}

Xu, Gaoya ^{[2
]}

Gao, Lixin ^{[2
]}

Xu, Lei ^{[2
]}

Zhou, Yubo ^{[2
]}

Gao, Jianrong ^{[1
]}

Ye, Qing ^{[1
]}

Li, Jia ^{[2
]}

机构：

[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

[3] Second People Hosp Xihu Dist, Hangzhou, Zhejiang, Peoples R China

来源：

ARCHIV DER PHARMAZIE | 2018年 / 351卷 / 10期

基金：

中国国家自然科学基金; 中国博士后科学基金;

关键词：

2-hydroxyglutaric acid; 3-(7-azaindoyl)-4-indolylmaleimides; isocitrate dehydrogenase 1 inhibitors; tumor; ACUTE MYELOID-LEUKEMIA; 2; MUTATIONS; SELECTIVE-INHIBITION; IDH2; IN-VIVO; GLIOMA; POTENT; CELLS; 2-HYDROXYGLUTARATE; LEUKEMOGENESIS;

D O I：

10.1002/ardp.201800039

中图分类号：

R914 [药物化学];

学科分类号：

100701 ;

摘要：

A series of 3-(7-azainodyl)-4-indolylmaleimides was designed, synthesized, and evaluated for their isocitrate dehydrogenase 1 (IDH1)/R132H inhibitory activities. Many compounds such as 11a, 11c, 11e, 11g, and 11s exhibited favorable inhibitory effects on IDH1/R132H and were highly selective against the wild-type IDH1. Evaluation of the biological activities at the cellular level showed that compounds 11a, 11c, 11e, 11g, and 11s could effectively suppress the production of 2-hydroxyglutaric acid in U87MG cells expressing IDH1/R132H. Preliminary structure-activity relationship (SAR) and molecular modeling studies were discussed based on the experimental data obtained. These findings may provide new insights into the development of novel IDH1/R132H inhibitors.

引用

页数：12

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