title: Development of a new class of aromatase inhibitors: design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives.
abstract: Aromatase (CYP19) catalyzes the aromatization reaction of androgen substrates to estrogens, the last and rate-limiting step in estrogen biosynthesis. Inhibition of aromatase is a new and promising approach to treat hormone-dependent breast cancer. We present here the design and development of isoflavanone derivatives as potential aromatase inhibitors. Structural modifications were performed on the A and B rings of isoflavanones via microwave-assisted, gold-catalyzed annulation reactions of hydroxyaldehydes and alkynes. The in vitro aromatase inhibition of these compounds was determined by fluorescence-based assays utilizing recombinant human aromatase (baculovirus/insect cell-expressed). The compounds 3-(4-phenoxyphenyl)chroman-4-one (1h), 6-methoxy-3-phenylchroman-4-one (2a) and 3-(pyridin-3-yl)chroman-4-one (3b) exhibited potent inhibitory effects against aromatase with IC(50) values of 2.4 μM, 0.26 μM and 5.8 μM, respectively. Docking simulations were employed to investigate crucial enzyme/inhibitor interactions such as hydrophobic interactions, hydrogen bonding and heme iron coordination. This report provides useful information on aromatase inhibition and serves as a starting point for the development of new flavonoid aromatase inhibitors.
authors.affiliation: Department of Chemistry, Northern Kentucky University, Nunn Drive, Highland Heights, KY 41099, United States.
authors.forename: Kevin
authors.initials: K
authors.lastname: Bonfield
authors.forename: Erica
authors.initials: E
authors.lastname: Amato
authors.forename: Tony
authors.initials: T
authors.lastname: Bankemper
authors.forename: Hannah
authors.initials: H
authors.lastname: Agard
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Steller
authors.forename: James M
authors.initials: JM
authors.lastname: Keeler
authors.forename: David
authors.initials: D
authors.lastname: Roy
authors.forename: Adam
authors.initials: A
authors.lastname: McCallum
authors.forename: Stefan
authors.initials: S
authors.lastname: Paula
authors.forename: Lili
authors.initials: L
authors.lastname: Ma
mesh_terms: D001141:Aromatase / Q000378:metabolism*; D047072:Aromatase Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D006801:Humans; D007529:Isoflavones / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D047072:Aromatase Inhibitors; D007529:Isoflavones; C065753:isoflavanone; D001141:Aromatase