AROMATASE INHIBITION BY FLAVONOIDS

Several synthetic flavones were found to inhibit the aromatization of androstenedione to estrone catalyzed by human placental microsomes. Twenty-one compounds were tested and the IC50 of the most active were: flavone, 10-mu-M; 7-hydroxyflavone, 0.5-mu-M; 7,4'-dihydroxyflavone, 2.0-mu-M; flavanone, 8.0-mu-M; and 4'-hydro? xyflavanone, 10-mu-M. Most of the others had IC50 values ranging from 80 to > 200-mu-M. These findings show that 4'-hydroxylation results in either no change or very little change in IC50 for flavanone, isoflavone and isoflavanone as well as other ring A hydroxylated flavones. Derivatives of flavone with a hydroxyl substituent at position 5, 6 and 7 were also screened. 7-Hydroxyflavone (11) was the most effective competitive inhibitor (IC50 = 0.5-mu-M) with an apparent Ki value of 0.25-mu-M. Compound 11 also induced a change in the absorption spectrum of the aromatase cytochrome P-450 which is indicative of substrate displacement. The relative binding affinities of the flavonoid analogs were determined and only ring A and ring B dihydroxylated analogs were found to bind to the estrogen receptor.