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 μM; 7-hydroxyflavone, 0.5 μM; 7,4′-dihydroxyflavone, 2.0 μM; flavanone, 8.0 μM; and 4′-hydroxyflavanone, 10 μM. Most of the others had IC₅₀ values ranging from 80 to 200 μM. 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-Hydroxy-flavone (11) was the most effective competitive inhibitor (IC₅₀=0.5 μM) with an apparent K_i value of 0.25 μM. 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.