Substituted quinolines as noncovalent proteasome inhibitors
Tanner J McDaniel1, Theresa A Lansdell1, Amila A Dissanayake1
1Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
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 5.4μM), representing a new class of nonpeptidic, noncovalent proteasome inhibitors.
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