文献类型：期刊文献

英文题名：Synthesis and Evaluation of 3-(Indol-3-yl)-4-(Pyrazolo[3,4-c]Pyridazin-3-yl)-Maleimides as Potent Mutant Isocitrate Dehydrogenase-1 Inhibitors

作者：Xu, Jianghong[1];Hu, Yuanyuan[1];Liu, Xiaoqi[1];Gao, Anhui[2];Gao, Lixin[2];Xu, Lei[2];Zhou, Yubo[2];Gao, Jianrong[1];Ye, Qing[1];Hu, Chunqi[3];Li, Ji[2]

机构：[1]Zhejiang Univ Technol, State Key Lab Breeding Base Green Chem Synth Tech, Hangzhou 310032, Peoples R China;[2]Chinese Acad Sci, Natl Ctr Drug Screening, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai, Peoples R China;[3]Shaoxing Univ, Coll Chem & Chem Engn, Shaoxing, Peoples R China

年份：2021

卷号：55

期号：7

起止页码：655

外文期刊名：PHARMACEUTICAL CHEMISTRY JOURNAL

收录：SCI-EXPANDED(收录号：WOS:000710310300005)、、Scopus(收录号：2-s2.0-85117443007)、WOS

基金：We gratefully acknowledge the Natural Science Foundation of Zhejiang (LY18H300009), the Postdoctoral Science Foundation of China (2014M550256), the State Key Laboratory of Drug Research (SIMM1601KF-04), National Natural Science Foundation of China (8150131067), "Personalized Medicines-Molecular Signature-based Drug Discovery and Development," Strategic Priority Research Program of the Chinese Academy of Sciences (XDA12020328).

语种：英文

外文关键词：IDH1-R132H inhibitors; synthesis; biological activity; docking; 3-(indol-3-yl)-4-(pyrazolo-[3; 4-c]pyridazin-3-yl)-maleimides

外文摘要：A series of new 3-(indol-3-yl)-4-(pyrazolo[3,4-c]pyridazin-3-yl)-maleimides were synthesized and evaluated for their inhibitory activity against IDH1-R132H. Most compounds exhibited significant potency to IDH1-R132H inhibition. Among these, 3-(1-(3-(1H-imidazol-1-yl)propyl)-6-bromo-1H-indol-3-yl)-4-(1-methyl-1H-pyrazolo[3,4-c]pyridazin-3-yl)-1H-pyrrole-2,5-dione (compound IXb), was the most promising IDH1-R132H inhibitor (IC50 = 0.031 mu M) and could significantly inhibit the production of 2-HG in U87MG IDH1-R132H cells. Preliminary structure-activity relationships and molecular modeling studies are discussed based on the experimental data obtained.