Substituted quinolines as noncovalent proteasome inhibitors

Bioorg Med Chem. 2016 Jun 1;24(11):2441-2450. doi: 10.1016/j.bmc.2016.04.005. Epub 2016 Apr 2.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Molecular Structure
  • Proteasome Endopeptidase Complex / metabolism*
  • Proteasome Inhibitors / chemical synthesis
  • Proteasome Inhibitors / chemistry
  • Proteasome Inhibitors / pharmacology*
  • Quinolines / chemical synthesis
  • Quinolines / chemistry
  • Quinolines / pharmacology*
  • Structure-Activity Relationship

Substances

  • Proteasome Inhibitors
  • Quinolines
  • Proteasome Endopeptidase Complex