title: Pyranoflavones: a group of small-molecule probes for exploring the active site cavities of cytochrome P450 enzymes 1A1, 1A2, and 1B1.
abstract: Selective inhibition of P450 enzymes is the key to block the conversion of environmental procarcinogens to their carcinogenic metabolites in both animals and humans. To discover highly potent and selective inhibitors of P450s 1A1, 1A2, and 1B1, as well as to investigate active site cavities of these enzymes, 14 novel flavone derivatives were prepared as chemical probes. Fluorimetric enzyme inhibition assays were used to determine the inhibitory activities of these probes toward P450s 1A1, 1A2, 1B1, 2A6, and 2B1. A highly selective P450 1B1 inhibitor 5-hydroxy-4'-propargyloxyflavone (5H4'FPE) was discovered. Some tested compounds also showed selectivity between P450s 1A1 and 1A2. α-Naphthoflavone-like and 5-hydroxyflavone derivatives preferentially inhibited P450 1A2, while β-naphthoflavone-like flavone derivatives showed selective inhibition of P450 1A1. On the basis of structural analysis, the active site cavity models of P450 enzymes 1A1 and 1A2 were generated, demonstrating a planar long strip cavity and a planar triangular cavity, respectively.
authors.affiliation: Department of Chemistry, Xavier University of Louisiana , 1 Drexel Drive, New Orleans, Louisiana 70125, USA.
authors.forename: Jiawang
authors.initials: J
authors.lastname: Liu
authors.forename: Shannon F
authors.initials: SF
authors.lastname: Taylor
authors.forename: Patrick S
authors.initials: PS
authors.lastname: Dupart
authors.forename: Corey L
authors.initials: CL
authors.lastname: Arnold
authors.forename: Jayalakshmi
authors.initials: J
authors.lastname: Sridhar
authors.forename: Quan
authors.initials: Q
authors.lastname: Jiang
authors.forename: Yuji
authors.initials: Y
authors.lastname: Wang
authors.forename: Elena V
authors.initials: EV
authors.lastname: Skripnikova
authors.forename: Ming
authors.initials: M
authors.lastname: Zhao
authors.forename: Maryam
authors.initials: M
authors.lastname: Foroozesh
mesh_terms: D001189:Aryl Hydrocarbon Hydroxylases / Q000187:drug effects*; D020134:Catalytic Domain / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1 / Q000187:drug effects*; D019388:Cytochrome P-450 CYP1A2 / Q000187:drug effects*; D065633:Cytochrome P-450 CYP1B1; D003627:Data Interpretation, Statistical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D047309:Flavones / Q000138:chemical synthesis* / Q000494:pharmacology*; D005470:Fluorometry; D006801:Humans; D007700:Kinetics; D008024:Ligands; D008958:Models, Molecular; D054852:Small Molecule Libraries; D013050:Spectrometry, Fluorescence; D013329:Structure-Activity Relationship
chemical_list: D004791:Enzyme Inhibitors; D047309:Flavones; D008024:Ligands; D054852:Small Molecule Libraries; D001189:Aryl Hydrocarbon Hydroxylases; C585496:CYP1B1 protein, human; D019363:Cytochrome P-450 CYP1A1; D019388:Cytochrome P-450 CYP1A2; D065633:Cytochrome P-450 CYP1B1