Estrogenic Activities of Isoflavones and Flavones and their Structure-Activity Relationships

In this study, we assessed the relationships between the structure and estrogenicity of flavonoid derivatives. We evaluated estrogenicity via yeast transactivation assays, E-screen assays, and ER binding assays. Genistein and coumestrol in the yeast transactivation assay and biochanin A, genistein, and equol in the E-screen assay, have been shown to have profound estrogenic activities. Flavonoids, with the exception of biochanin A and daidzein, exhibit more profound selectivity for ERβ than for ERα. We compared several flavonoids in terms of estrogenicity, as well as relatively small structural differences including the position of the phenol ring and hydroxy groups, the substitution of hydroxy groups or methoxy groups, the opening of the phenol ring; glycitein vs. 4′,6,7-trihydroxyisoflavone, biochanin A vs. genistein, apigenin vs. genistein, 7,4′-dihydroxyflavone vs. isoliquiritigenin. A quantitative structure-activity relationship study design was utilized to develop model equations for the estrogenic activities of flavonoid derivatives. The prediction of estrogenicity with regard to ERα shows a positive correlation with MW and AlogP, and a negative correlation with Apol and Area (r 2 = 0.89 and q 2 = 0.83). The prediction of estrogenicity with regard to ERβ reveals a positive correlation with the AlogP and Hbond acceptors, and a negative correlation with RadOfGyration (r 2 = 0.77 and q 2 = 0.72). Abbreviations AlogP:log of the partition coefficient Apol:sum of atomic polarizabilities CD-FBS:charcoal-dextran-treated fetal bovine serum E2:17β-estradiol ER:estrogen receptor GFA:genetic function approximation Hbond acceptor:number of H bond acceptors LOO:leave-one-out MTT:3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide MW:molecular weight O.D.:optical density QSAR:quantitative structure-activity relationship RadOfGyration:radius of gyration RBA:relative binding affinity Rotlbonds:number of rotatable bonds