Design, synthesis and evaluation of the inhibitory selectivity of novel trans-resveratrol analogues on human recombinant CYP1A1, CYP1A2 and CYP1B1
| Autor: | Agnes M. Rimando, Renata Mikstacka, Tomasz Stefański, Zbigniew Dutkiewicz, Stanisław Sobiak |
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| Rok vydání: | 2012 |
| Předmět: |
Models
Molecular Molecular model Cytochrome P-450 CYP1A2 Inhibitors Stereochemistry Clinical Biochemistry Substituent Pharmaceutical Science Biochemistry Isozyme Structure-Activity Relationship chemistry.chemical_compound Cytochrome P-450 CYP1A2 Stilbenes Drug Discovery Cytochrome P-450 CYP1A1 medicine Humans Structure–activity relationship Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Cytochrome P450 NADPH oxidation Recombinant Proteins Enzyme Mechanism of action chemistry Resveratrol Drug Design Cytochrome P-450 CYP1B1 biology.protein Molecular Medicine Aryl Hydrocarbon Hydroxylases medicine.symptom |
| Zdroj: | Bioorganic & Medicinal Chemistry. 20:5117-5126 |
| ISSN: | 0968-0896 |
| DOI: | 10.1016/j.bmc.2012.07.012 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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