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 microM; 7-hydroxyflavone, 0.5 microM; 7,4'-dihydroxyflavone, 2.0 microM; flavanone, 8.0 microM; and 4'-hydroxyflavanone, 10 microM. Most of the others had IC50 values ranging from 80 to greater than 200 microM. 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 microM) with an apparent Ki value of 0.25 microM. 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 adn ring B dihydroxylated analogs were found to bind to the estrogen receptor.
Ibrahim
A R
AR
Department of Medicinal Chemistry, College of Pharmacy, University of Minnesota, Minneapolis 55455.
Abul-Hajj
Y J
YJ
D000818:Animals; D047072:Aromatase Inhibitors; D005260:Female; D005419:Flavonoids / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D007700:Kinetics; D008861:Microsomes / Q000201:enzymology; D015394:Molecular Structure; D010920:Placenta / Q000201:enzymology*; D011247:Pregnancy; D051381:Rats; D011960:Receptors, Estrogen / Q000378:metabolism; D013329:Structure-Activity Relationship; D014599:Uterus / Q000378:metabolism
D047072:Aromatase Inhibitors; D005419:Flavonoids; D011960:Receptors, Estrogen