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Substituted quinolines as noncovalent proteasome inhibitors.

ABSTRACT: 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 5.4?M), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.

SUBMITTER: McDaniel TJ

PROVIDER: S-EPMC5724766 | biostudies-literature | 2016 Jun

REPOSITORIES: biostudies-literature

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Substituted quinolines as noncovalent proteasome inhibitors.

McDaniel Tanner J TJ Lansdell Theresa A TA Dissanayake Amila A AA Azevedo Lauren M LM Claes Jacob J Odom Aaron L AL Tepe Jetze J JJ

Bioorganic & medicinal chemistry 20160402 11

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 proteo ...[more]

PMID: 27112450

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