title: Thiomethylstilbenes as inhibitors of CYP1A1, CYP1A2 and CYP1B1 activities.
abstract: Resveratrol (3,5,4'-trihydroxy-trans-stilbene) is a natural stilbene derivative occurring in grapes, peanuts and red wine. Its chemopreventive action has been established in studies on animal models. Recently, numerous classes of compounds with stilbene backbone have been investigated for their biological activity concerning cancer prevention; e. g. resveratrol methyl ethers appeared to be specific and potent inhibitors of cytochromes P450 (CYP) family 1 involved in the activation of procarcinogens. Since the replacement of the 4'-hydroxyl with a thiomethyl group is supposed to reduce toxicity of stilbene derivatives, the purpose of this study was the synthesis and evaluation of a series of 4-thiomethyl-trans-stilbene derivatives differing in a number and position of additional methoxy groups. Their inhibitory potency toward human recombinant CYPs: CYP1A1, CYP1A2 and CYP1B1 have been studied and compared with the effect of resveratrol and its analogues. Among compounds tested, 2-methoxy-4'-thiomethyl-trans-stilbene and 3-methoxy-4'-thiomethyl-trans-stilbene demonstrated the most potent and selective inhibitory effect on CYP1A1 and CYP1B1 activities. The results of our study indicate that modification of stilbene derivatives with thiomethyl group may influence the selectivity and inhibitory potency of these compounds toward P450 isozymes. Thus, it should be considered in developing new chemopreventive agents based on their mechanism of action.
authors.affiliation: Department of Pharmaceutical Biochemistry, Poznan University of Medical Sciences, Poznan, Poland. rmikstac@amp.edu.pl
authors.forename: Renata
authors.initials: R
authors.lastname: Mikstacka
authors.forename: Wanda
authors.initials: W
authors.lastname: Baer-Dubowska
authors.forename: Marcin
authors.initials: M
authors.lastname: Wieczorek
authors.forename: Stanislaw
authors.initials: S
authors.lastname: Sobiak
mesh_terms: D000818:Animals; D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors*; D019363:Cytochrome P-450 CYP1A1 / Q000037:antagonists & inhibitors*; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D065633:Cytochrome P-450 CYP1B1; D004791:Enzyme Inhibitors / Q000494:pharmacology; D007313:Insecta; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology*; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000494:pharmacology*; D013440:Sulfides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C000601815:3-methoxy-4'-methylthiostilbene; D065609:Cytochrome P-450 CYP1A2 Inhibitors; D004791:Enzyme Inhibitors; D013267:Stilbenes; D013440:Sulfides; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D065633:Cytochrome P-450 CYP1B1; D000077185:Resveratrol