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

Sarah E. St. John, Katherine C. Jensen, Soosung Kang, Yafang Chen, Barbara Calamini, Andrew D. Mesecar, Mark A. Lipton

Research output: Contribution to journalArticlepeer-review

19 Scopus citations

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.

Original languageEnglish
Pages (from-to)6022-6037
Number of pages16
JournalBioorganic and Medicinal Chemistry
Volume21
Issue number19
DOIs
StatePublished - 1 Oct 2013

Keywords

  • Inhibitors
  • Library
  • Organic synthesis
  • Quinone reductase 2
  • Resveratrol
  • X-ray crystallography

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