SAR Study on Estrogen Receptor / Activity of (Iso)flavonoids: Importance of Prenylation, C-Ring (Un)Saturation, and Hydroxyl Substituents

Many botanicals used for women's health contain estrogenic (iso)flavonoids. The literature suggests that estrogen receptor beta (ER beta) activity can counterbalance estrogen receptor alpha (ER alpha)-mediated proliferation, thus providing a better safety profile. A structure-activity relationship study of (iso)flavonoids was conducted to identify ER beta-preferential structures, overall estrogenic activity, and ER subtype estrogenic activity of botanicals containing these (iso)flavonoids. Results showed that flavonoids with prenylation on C8 position increased estrogenic activity. C8-prenylated flavonoids with C2-C3 unsaturation resulted in increased ER beta potency and selectivity [e.g., 8-prenylapigenin (8-PA), EC50 (ER beta): 0.0035 +/- 0.00040 mu M], whereas 4'-methoxy or C3 hydroxy groups reduced activity [e.g., icaritin, EC50 (ER beta): 1.7 +/- 0.70 mu M]]. However, nonprenylated and C2-C3 unsaturated isoflavonoids showed increased ER beta estrogenic activity [e.g., genistein, EC50 (ER beta): 0.0022 +/- 0.0004 mu M]. Licorice (Glycyrrhiza inflata, [EC50 (ER alpha): 1.1 +/- 0.20; (ER beta): 0.60 +/- 0.20 mu g/mL], containing 8-PA, and red clover [EC50 (ER alpha): 1.8 +/- 0.20; (ER beta): 0.45 +/- 0.10 mu g/mL], with genistein, showed ER beta-preferential activity as opposed to hops [EC50 (ER alpha): 0.030 +/- 0.010; (ER beta): 0.50 +/- 0.050 mu g/mL] and Epimedium sagittatum [EC50 (ER alpha): 3.2 +/- 0.20; (ER beta): 2.5 +/- 0.090 mu g/mL], containing 8-prenylnaringenin and icaritin, respectively. Botanicals with ER beta-preferential flavonoids could plausibly contribute to ER beta-protective benefits in menopausal women.