title: Optimization of thiazole analogues of resveratrol for induction of NAD(P)H:quinone reductase 1 (QR1).
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.
authors.affiliation: Department of Medicinal Chemistry and Molecular Pharmacology, College of Pharmacy, and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
authors.forename: Abdelrahman S
authors.initials: AS
authors.lastname: Mayhoub
authors.forename: Laura
authors.initials: L
authors.lastname: Marler
authors.forename: Tamara P
authors.initials: TP
authors.lastname: Kondratyuk
authors.forename: Eun-Jung
authors.initials: EJ
authors.lastname: Park
authors.forename: John M
authors.initials: JM
authors.lastname: Pezzuto
authors.forename: Mark
authors.initials: M
authors.lastname: Cushman
mesh_terms: D000818:Animals; D004790:Enzyme Induction / Q000187:drug effects; D057809:HEK293 Cells; D006801:Humans; D008264:Macrophages / Q000187:drug effects; D051379:Mice; D016660:NAD(P)H Dehydrogenase (Quinone) / Q000096:biosynthesis* / Q000378:metabolism; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*
chemical_list: D013267:Stilbenes; D013844:Thiazoles; D016660:NAD(P)H Dehydrogenase (Quinone); D000077185:Resveratrol