Design, synthesis, biological and structural evaluation of functionalized resveratrol analogues as inhibitors of quinone reductase 2

Bioorg Med Chem. 2013 Oct 1;21(19):6022-37. doi: 10.1016/j.bmc.2013.07.037. Epub 2013 Jul 27.

Abstract

Resveratrol (3,5,4'-trihydroxylstilbene) has been proposed to elicit a variety of positive health effects including protection against cancer and cardiovascular disease. The highest affinity target of resveratrol identified so far is the oxidoreductase enzyme quinone reductase 2 (QR2), which is believed to function in metabolic reduction and detoxification processes; however, evidence exists linking QR2 to the metabolic activation of quinones, which can lead to cell toxicity. Therefore, inhibition of QR2 by resveratrol may protect cells against reactive intermediates and eventually cancer. With the aim of identifying novel inhibitors of QR2, we designed, synthesized, and tested two generations of resveratrol analogue libraries for inhibition of QR2. In addition, X-ray crystal structures of six of the resveratrol analogues in the active site of QR2 were determined. Several novel inhibitors of QR2 were successfully identified as well as a compound that inhibits QR2 with a novel binding orientation.

Keywords: Inhibitors; Library; Organic synthesis; Quinone reductase 2; Resveratrol; X-ray crystallography.

Publication types

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

MeSH terms

  • Anilides / chemistry
  • Catalytic Domain
  • Crystallography, X-Ray
  • Drug Design*
  • Enzyme Activation / drug effects
  • Enzyme Inhibitors / chemistry*
  • Enzyme Inhibitors / pharmacology*
  • Humans
  • Inhibitory Concentration 50
  • Molecular Structure
  • Quinone Reductases / antagonists & inhibitors*
  • Resveratrol
  • Small Molecule Libraries
  • Stilbenes / chemical synthesis
  • Stilbenes / chemistry*
  • Stilbenes / pharmacology

Substances

  • Anilides
  • Enzyme Inhibitors
  • Small Molecule Libraries
  • Stilbenes
  • benzanilide
  • NRH - quinone oxidoreductase2
  • Quinone Reductases
  • Resveratrol