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United States Department of Agriculture

Agricultural Research Service

Research Project: Chemistry of Natural Products for Nutraceutical Use, Pest Management and Crop Development

Location: Natural Products Utilization Research

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

Authors
item Mikstacka, Renata -
item Rimando, Agnes
item Dutkiewicz, Zbigniew -
item Stefanski, Tomasz -
item Sobiak, Stanislaw -

Submitted to: Bioorganic and Medicinal Chemistry
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: July 6, 2012
Publication Date: July 16, 2012
Citation: Mikstacka, R., Rimando, A.M., Dutkiewicz, Z., Stefanski, T., Sobiak, S. 2012. Design synthesis and evaluation of the inhibitory selectivity of novel trans-resveratrol analogues on human recombinant CYP1A1 CYP1A2 and CYP1B1. Bioorganic and Medicinal Chemistry. 20(17):5117-2126.

Interpretive Summary: Stilbene compounds were synthesized and evaluated for their activity to inhibit three forms of the enzyme cytochrome p450: CYP1A1, CYP1A2, and CYP1B1. In humans, these enzymes act on some compounds converting these compounds to products that could cause cancer. Among the stilbenes synthesized, one analog (3,4,5-trimethoxy-4’-thiomethyl-trans-stilbene) was effective in inhibiting all three forms of cytochrome p450. Another compound synthesized (2,3,4-trimethoxy-4’-thiomethyl-trans-stilbene) appeared to be the most selective inhibitor of CYP1A1 and CYP1B1. Molecular modeling studies showed the pose of the compound in the active site of CYP1A2. Chemical analysis also showed the product from reaction of the enzyme, showing addition of an OH group. Structure-activity relationship study rendered better understanding of the mechanism of action of the enzymes crucial at the early stage of carcinogenesis.

Technical Abstract: A series of trans-stilbene derivatives containing 4’-thiomethyl 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’-thiomethyl-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’-thiomethyl-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 thiomethylstilbene 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 mono-hydroxylated 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.

Last Modified: 4/19/2014
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