Optimization of thiazole analogues of resveratrol for induction of NAD(P)H:quinone reductase 1 (QR1)

Bioorg Med Chem. 2012 Dec 15;20(24):7030-9. doi: 10.1016/j.bmc.2012.10.006.

Abdelrahman S Mayhoub ¹, Laura Marler, Tamara P Kondratyuk, Eun-Jung Park, John M Pezzuto, Mark Cushman

Affiliations

Affiliation

1 Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.

PMID: 23142320 DOI: 10.1016/j.bmc.2012.10.006

Abstract

NAD(P)H:quinone reductase 1 (QR1) belongs to a class of Enzymes called cytoprotective Enzymes. It exhibits its Cancer protective activity mainly by inhibiting the formation of intracellular semiquinone radicals, and by generating α-tocopherolhydroquinone, which acts as a free radical scavenger. It is therefore believed that QR1 inducers can act as Cancer chemopreventive agents. Resveratrol (1) is a naturally occurring stilbene derivative that requires a concentration of 21 μM to double QR1 activity (CD = 21 μM). The stilbene double bond of resveratrol was replaced with a thiadiazole ring and the Phenols were eliminated to provide a more potent and selective derivative 2 (CD = 2.1 μM). Optimizing the substitution pattern of the two phenyl rings and the central heterocyclic linker led to a highly potent and selective QR1 inducer 9o with a CD value of 0.087 μM.

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