title: Benzotropolone inhibitors of estradiol methylation: kinetics and in silico modeling studies.
abstract: Natural and synthetic benzotropolone compounds were assessed in vitro for their ability to inhibit hydroxyestradiol methylation by catechol-O-methyltransferase (COMT). The compounds were also modeled in silico with a homology model of human COMT. Purpurogallin (1), purpurogallin carboxylic acid (2), and theaflavin-3,3'-digallate (6) were the most potent inhibitors of 2-hydroxy and 4-hydroxyestradiol methylation (IC(50) 0.22-0.50microM). Compounds 1 and 6 decreased the V(max) and increased the K(m) of COMT, indicating a mixed-type inhibition. Compounds 1 and 2 bound to COMT by inserting the six-membered ring of the benzotropolone into the active site. Decreased acidity of the hydroxyl groups on this ring or increased bulkiness reduced potency. Compound 6 bound by inserting the galloyl ester into the active site, which allowed the compound to overcome increased bulkiness and resulted in restored potency. Further studies are needed to determine the impact in vivo of COMT inhibition by these compounds.
authors.affiliation: Department of Chemical Biology Rutgers, Ernest Mario School of Pharmacy, The State University of New Jersey, 164 Frelinghuysen Rd, Piscataway, NJ 08854, USA.
authors.forename: Joshua D
authors.initials: JD
authors.lastname: Lambert
authors.forename: Dapeng
authors.initials: D
authors.lastname: Chen
authors.forename: Ching Y
authors.initials: CY
authors.lastname: Wang
authors.forename: Ni
authors.initials: N
authors.lastname: Ai
authors.forename: Shengmin
authors.initials: S
authors.lastname: Sang
authors.forename: Chi-Tang
authors.initials: CT
authors.lastname: Ho
authors.forename: William J
authors.initials: WJ
authors.lastname: Welsh
authors.forename: Chung S
authors.initials: CS
authors.lastname: Yang
mesh_terms: D065098:Catechol O-Methyltransferase Inhibitors; D002851:Chromatography, High Pressure Liquid / Q000379:methods; D003198:Computer Simulation; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D004958:Estradiol / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D008745:Methylation; D008958:Models, Molecular; D008968:Molecular Conformation; D008969:Molecular Sequence Data; D009942:Organometallic Compounds / Q000737:chemistry / Q000494:pharmacology; D011485:Protein Binding; D011487:Protein Conformation; D013329:Structure-Activity Relationship; D014334:Tropolone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D065098:Catechol O-Methyltransferase Inhibitors; D004791:Enzyme Inhibitors; D009942:Organometallic Compounds; D004958:Estradiol; D014334:Tropolone