Synthesis and biological evaluation of novel 4-azaindolyl-indolyl-maleimides as glycogen synthase kinase-3beta (GSK-3beta) inhibitors.
A series of novel 4-azaindolyl-indolyl-maleimides were synthesized and evaluated for their GSK-3beta inhibitory activity. Most compounds exhibited high potency to GSK-3beta. Among them, compound 7c was the most promising GSK-3beta inhibitor. Preliminary structure-activity relationships were discussed based on the experimental data obtained and showed that different substituents on the indole ring and side chains at 1-position of indole had varying degrees of influence on the GSK-3beta inhibitory potency. In a cell-based functional assay, compounds 7c and 15a significantly reduced Abeta-induced Tau hyperphosphorylation by inhibiting GSK-3beta.
Ye
Qing
Q
ZJU-ENS Joint Laboratory of Medicinal Chemistry, College of Pharmaceutical Sciences, Zhejiang University, Hangzhou, China.
Xu
Guiqing
G
Lv
Dan
D
Cheng
Zhe
Z
Li
Jia
J
Hu
Yongzhou
Y
D045744:Cell Line, Tumor; D038362:Glycogen Synthase Kinase 3 / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D008301:Maleimides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008958:Models, Molecular; D009447:Neuroblastoma / Q000201:enzymology; D010766:Phosphorylation / Q000187:drug effects; D013329:Structure-Activity Relationship; D016875:tau Proteins / Q000378:metabolism
D008301:Maleimides; D016875:tau Proteins; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; D038362:Glycogen Synthase Kinase 3