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.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Amyloid beta-Peptides / genetics
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Amyloid beta-Peptides / metabolism
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Cell Line, Tumor
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Glycogen Synthase Kinase 3 / antagonists & inhibitors*
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Glycogen Synthase Kinase 3 / genetics
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Glycogen Synthase Kinase 3 / metabolism
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Glycogen Synthase Kinase 3 beta
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Humans
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Molecular Docking Simulation
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Phosphorylation / drug effects
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Protein Kinase Inhibitors* / chemical synthesis
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Protein Kinase Inhibitors* / chemistry
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Protein Kinase Inhibitors* / pharmacology
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Structure-Activity Relationship
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tau Proteins / genetics
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tau Proteins / metabolism
Substances
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Amyloid beta-Peptides
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MAPT protein, human
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Protein Kinase Inhibitors
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tau Proteins
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GSK3B protein, human
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Glycogen Synthase Kinase 3 beta
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Glycogen Synthase Kinase 3