Effect of substituent size and dimensionality on potency of phenolic xenoestrogens

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 (EC50−1)]. There is a trend of an increase in estrogenicity with an increase in substituent size. Selected size parameters (molecular volume and molar refractivity), Verloopʹs sterimol shape parameters (L and B5) and the fourth order path/cluster molecular connectivity index were found to be correlate poorly (r2 ≈0.65) with estrogenicity. The r2 value of the order of the path, versus log (EC50−1) showed parabolic relationships. The third order path index (r2 > 0.80) provided the best fit with the estrogenicity.