Substituted quinolines as noncovalent proteasome inhibitors

[Display omitted] Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrim...

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Bibliographic Details
Published in:Bioorganic & medicinal chemistry 2016-06, Vol.24 (11), p.2441-2450
Main Authors: McDaniel, Tanner J., Lansdell, Theresa A., Dissanayake, Amila A., Azevedo, Lauren M., Claes, Jacob, Odom, Aaron L., Tepe, Jetze J.
Format: Article
Language:English
Subjects:
Dose-Response Relationship, Drug
HeLa Cells
Humans
Inhibitors
Molecular Structure
Noncovalent
Proteasome
Proteasome Endopeptidase Complex - metabolism
Proteasome Inhibitors - chemical synthesis
Proteasome Inhibitors - chemistry
Proteasome Inhibitors - pharmacology
Quinolines
Quinolines - chemical synthesis
Quinolines - chemistry
Quinolines - pharmacology
Structure-Activity Relationship
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Summary:[Display omitted] Screening of a library of diverse heterocyclic scaffolds identified substituted quinolines as inhibitors of the human proteasome. The heterocyclic library was prepared via a novel titanium-catalyzed multicomponent coupling reaction, which rendered a diverse set of isoxazoles, pyrimidines, pyrroles, pyrazoles and quinolines. SAR of the parent lead compound indicated that hydrophobic residues on the benzo-moiety significantly improved potency. Lead compound 25 inhibits the chymotryptic-like proteolytic activity of the proteasome (IC50 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
ISSN:0968-0896
1464-3391
DOI:10.1016/j.bmc.2016.04.005