Substituted quinolines as noncovalent proteasome inhibitors

  • Bioorg Med Chem. 2016 Jun 1;24(11):2441-2450. doi: 10.1016/j.bmc.2016.04.005.
Tanner J McDaniel  1 ,  Theresa A Lansdell  1 ,  Amila A Dissanayake  1 ,  Lauren M Azevedo  1 ,  Jacob Claes  1 ,  Aaron L Odom  2 ,  Jetze J Tepe  3
Affiliations
  • 1. Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States.
  • 2. Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States. Electronic address: [email protected].
  • 3. Department of Chemistry, Michigan State University, East Lansing, MI 48824, United States. Electronic address: [email protected].
PMID: 27112450 DOI: 10.1016/j.bmc.2016.04.005
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.

Keywords
Inhibitors; Noncovalent; Proteasome; Quinolines.