Effect of substituent size and dimensionality on potency of phenolic xenoestrogens

Abstract

Previous results show the position, size, and shape of the non-phenolic moiety of xenoestrogen effect potency. Para-substituted compounds were more potent than meta-substituted ones, which in turn were more potent than ortho-substituted compounds. A minimum three-carbon-moiety is required for activity and tertiary-branched or highly substituted congeners were more potent than secondary/normal or less substituted ones. In an effort to quantify the relationship between size/shape of the non-phenolic moiety and estrogenic potency, a series of substituted phenols were evaluated and activity was correlated with a series of bulk and shape parameters. The Saccharomyces cerevisiae-based Lac-Z reporter assay was then used and estrogenicity reported as the logarithm of the inverse of the 50% β-galactosidase activity [log (EC 50 −1)]. There is a trend of an increase in estrogenicity with an increase in substituent size. Selected size parameters (molecular volume and molar refractivity), Verloop's sterimol shape parameters (L and B 5) and the fourth order path/cluster molecular connectivity index were found to be correlate poorly ( r 2 ≈0.65) with estrogenicity. The r 2 value of the order of the path, versus log (EC 50 −1) showed parabolic relationships. The third order path index ( r 2 > 0.80) provided the best fit with the estrogenicity.