Design, synthesis and evaluation of the inhibitory selectivity of novel trans-resveratrol analogues on human recombinant CYP1A1, CYP1A2 and CYP1B1

• Published in: Bioorganic & medicinal chemistry 2012-09, Vol.20 (17), p.5117-5126
• Main Authors: Mikstacka, Renata, Rimando, Agnes M., Dutkiewicz, Zbigniew, Stefański, Tomasz, Sobiak, Stanisław
• Format: Article
• Language: English
• Subjects: active sites; Aryl Hydrocarbon Hydroxylases - antagonists & inhibitors; Aryl Hydrocarbon Hydroxylases - metabolism; Biological and medical sciences; carcinogenesis; CYP1A1; CYP1A2; CYP1A2 protein; CYP1B1; cytochrome P-450; Cytochrome P-450 CYP1A1 - antagonists & inhibitors; Cytochrome P-450 CYP1A1 - metabolism; Cytochrome P-450 CYP1A2 - metabolism; Cytochrome P-450 CYP1A2 Inhibitors; Cytochrome P-450 CYP1B1; Cytochrome P450; Dose-Response Relationship, Drug; Drug Design; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; enzymes; heme iron; Humans; isozymes; mechanism of action; Medical sciences; Metabolism; Models, Molecular; Molecular docking; Molecular Structure; NADP; NADP (coenzyme); Oxidation; P450; Pharmacology. Drug treatments; Recombinant Proteins - antagonists & inhibitors; Recombinant Proteins - metabolism; Resveratrol; Stilbenes - chemical synthesis; Stilbenes - chemistry; Stilbenes - pharmacology; Structure-Activity Relationship; structure-activity relationships; trans-stilbene; trans-Stilbene derivatives
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/j.bmc.2012.07.012

A series of trans-stilbene derivatives containing 4′-methylthio substituent were synthesized and evaluated for inhibitory activities on human recombinant cytochrome P450(s): CYP1A1, CYP1A2, and CYP1B1. CYP1A2-related metabolism of stilbene derivatives was estimated by using NADPH oxidation assay. Additionally, for CYP1A2 and CYP1B1 molecular docking analysis was carried out to provide information on enzyme–ligand interactions and putative site of metabolism. 3,4,5-Trimethoxy-4′-methylthio-trans-stilbene, an analogue of DMU-212 (3,4,5,4′-tetramethoxy-trans-stilbene) was an effective inhibitor of all CYP1 enzymes. On the other hand, 2,3,4-trimethoxy-4′-methylthio-trans-stilbene, appeared to be the most selective inhibitor of the isozymes CYP1A1 and CYP1B1, displaying extremely low affinity towards CYP1A2. Molecular modeling suggested that the most probable binding poses of the methylthiostilbene derivatives in CYP1A2 active sites are those with the methylthio substituent directed towards the heme iron. Products of CYP1A2-catalyzed oxidation of 2,4,5-trimethoxy-4′-methylthiostilbene and 3,4,5-trimethoxy-4′-methylthiostilbene were identified as monohydroxylated compounds. Other studied derivatives appeared to be poor substrates of CYP1A2. Structure–activity relationship analysis rendered better understanding of the mechanism of action of xenobiotic-metabolizing enzymes crucial at the early stage of carcinogenesis.