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

Abstract

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 (r² = 0.89 and q² = 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 (r² = 0.77 and q² = 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

Key words

Isoflavones - Flavones - Yeast transactivation assay - E-screen assay - ER binding assay - QSAR

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