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

doi:10.1016/j.bmc.2013.07.037

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

Department of Pharmaceutical Sciences

Research output: Contribution to journal › Article › peer-review

23 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 language	English
Pages (from-to)	6022-6037
Number of pages	16
Journal	Bioorganic and Medicinal Chemistry
Volume	21
Issue number	19
DOIs	https://doi.org/10.1016/j.bmc.2013.07.037
State	Published - 1 Oct 2013

Bibliographical note

Funding Information:
Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817 ). K.C.J. acknowledges support by the National Institute of Health Biophysics Training Grant T32 GM008296 (NIH/GM). This research was supported in part by Grants from the Walther Cancer Foundation (to A.D.M) and the NIH (NCI CA48112 to A.D.M.) We would also like to acknowledge support from the Macromolecular Crystallography Shared Research Facility via the Purdue University Center for Cancer Research.

Keywords

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

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

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",

author = "{St. John}, {Sarah E.} and Jensen, {Katherine C.} and Soosung Kang and Yafang Chen and Barbara Calamini and Mesecar, {Andrew D.} and Lipton, {Mark A.}",

note = "Funding Information: Use of the Advanced Photon Source, an Office of Science User Facility operated for the U.S. Department of Energy (DOE) Office of Science by Argonne National Laboratory, was supported by the U.S. DOE under Contract No. DE-AC02-06CH11357. Use of the LS-CAT Sector 21 was supported by the Michigan Economic Development Corporation and the Michigan Technology Tri-Corridor (Grant 085P1000817 ). K.C.J. acknowledges support by the National Institute of Health Biophysics Training Grant T32 GM008296 (NIH/GM). This research was supported in part by Grants from the Walther Cancer Foundation (to A.D.M) and the NIH (NCI CA48112 to A.D.M.) We would also like to acknowledge support from the Macromolecular Crystallography Shared Research Facility via the Purdue University Center for Cancer Research. ",

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AU - Mesecar, Andrew D.

AU - Lipton, Mark A.

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

Abstract

Bibliographical note

Keywords

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