title: Synthetic models related to methoxalen and menthofuran-cytochrome P450 (CYP) 2A6 interactions. benzofuran and coumarin derivatives as potent and selective inhibitors of CYP2A6.
abstract: Human microsomal cytochrome P450 (CYP) 2A6 contributes extensively to nicotine detoxication but also activates tobacco-specific procarcinogens to mutagenic products. We prepared a series of benzofuran and coumarin derivatives that have inhibitory effects on the activity of human CYP2A6. The reported compounds methoxalen and menthofuran had potent inhibitory effects on the activity of CYP2A6 with IC50 values of 0.47 µM and 1.27 µM, respectively. Synthetic benzofuran (4-methoxybenzofuran: IC₅₀=2.20 µM) and coumarin (5-methoxycoumarin: IC₅₀=0.13 µM and 6-methoxycoumarin: IC₅₀=0.64 µM) derivatives, which have more selective effects than those of methoxalen and menthofuran, exhibited comparable activities against CYP2A6. These compounds can be used as a lead compounds in the design of CYP2A6 inhibitor drugs to reduce smoking and tobacco-related cancers.
authors.affiliation: Faculty of Pharmaceutical Sciences, Health Sciences University of Hokkaido.
authors.forename: Yuki
authors.initials: Y
authors.lastname: Yamaguchi
authors.forename: Ichie
authors.initials: I
authors.lastname: Akimoto
authors.forename: Kyoko
authors.initials: K
authors.lastname: Motegi
authors.forename: Teruki
authors.initials: T
authors.lastname: Yoshimura
authors.forename: Keiji
authors.initials: K
authors.lastname: Wada
authors.forename: Naozumi
authors.initials: N
authors.lastname: Nishizono
authors.forename: Kazuaki
authors.initials: K
authors.lastname: Oda
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D001572:Benzofurans / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D003374:Coumarins / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D065637:Cytochrome P-450 CYP2A6; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D008956:Models, Chemical; D039821:Monoterpenes / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding
chemical_list: D001572:Benzofurans; D003374:Coumarins; D004791:Enzyme Inhibitors; D039821:Monoterpenes; C588045:methoxalen; C054487:menthofuran; C030123:coumarin; D001189:Aryl Hydrocarbon Hydroxylases; C585710:CYP2A6 protein, human; D065637:Cytochrome P-450 CYP2A6; C105430:benzofuran