Development of a new class of aromatase inhibitors: design, synthesis and inhibitory activity of 3-phenylchroman-4-one (isoflavanone) derivatives

Bioorg Med Chem. 2012 Apr 15;20(8):2603-13. doi: 10.1016/j.bmc.2012.02.042. Epub 2012 Feb 27.


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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aromatase / metabolism*
  • Aromatase Inhibitors / chemical synthesis
  • Aromatase Inhibitors / chemistry
  • Aromatase Inhibitors / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Humans
  • Isoflavones / chemical synthesis
  • Isoflavones / chemistry
  • Isoflavones / pharmacology*
  • Molecular Structure
  • Structure-Activity Relationship


  • Aromatase Inhibitors
  • Isoflavones
  • isoflavanone
  • Aromatase