title: Synthesis and biological evaluation of 3-benzisoxazolyl-4-indolylmaleimides as potent, selective inhibitors of glycogen synthase kinase-3β.
abstract: A series of novel 3-benzisoxazolyl-4-indolyl-maleimides were synthesized and evaluated for their GSK-3β inhibitory activity. Most compounds exhibited high inhibitory potency towards GSK-3β. Among them, compound 7j with an IC₅₀ value of 0.73 nM was the most promising GSK-3β inhibitor. Preliminary structure-activity relationships were examined and showed that different substituents on the indole ring and N¹-position of the indole ring had varying degrees of influence on the GSK-3β inhibitory potency. Compounds 7c, 7f, 7j-l and 7o-q could obviously reduce Aβ-induced Tau hyperphosphorylation by inhibiting GSK-3β in a cell-based functional assay.
authors.affiliation: State Key Laboratory Breeding Base of Green Chemistry-Synthesis Technology, Zhejiang University of Technology, Hangzhou 310032, Zhejiang, China.
authors.forename: Qing
authors.initials: Q
authors.lastname: Ye
authors.forename: Meng
authors.initials: M
authors.lastname: Li
authors.forename: Yubo
authors.initials: Y
authors.lastname: Zhou
authors.forename: Tao
authors.initials: T
authors.lastname: Pang
authors.forename: Lei
authors.initials: L
authors.lastname: Xu
authors.forename: Jiayi
authors.initials: J
authors.lastname: Cao
authors.forename: Liang
authors.initials: L
authors.lastname: Han
authors.forename: Yujin
authors.initials: Y
authors.lastname: Li
authors.forename: Weisi
authors.initials: W
authors.lastname: Wang
authors.forename: Jianrong
authors.initials: J
authors.lastname: Gao
authors.forename: Jia
authors.initials: J
authors.lastname: Li
mesh_terms: D016229:Amyloid beta-Peptides / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D062105:Molecular Docking Simulation; D010766:Phosphorylation / Q000187:drug effects; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: D016229:Amyloid beta-Peptides; C054369:MAPT protein, human; D047428:Protein Kinase Inhibitors; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3