Structure-activity relationships for a large diverse set of natural, synthetic, and environmental estrogens

Understanding structural requirements for a chemical to exhibit estrogen re ceptor (ER) binding has been important in various fields. This knowledge ha s been directly and indirectly applied to design drugs for human estrogen r eplacement therapy, and to identify estrogenic endocrine disrupters. This p aper reports structure-activity relationships (SARs) based on a total of 23 0 chemicals, including both natural and xenoestrogens. Activities were gene rated using a validated ER competitive binding assay, which covers a 10(6)- fold range. This study is focused on identification of structural commonali ties among diverse ER ligands. It provides an overall picture of how xenoes trogens structurally resemble endogenous 17 beta -estradiol (E-2) and the s ynthetic estrogen diethylstilbestrol (DES). On the basis of SAR analysis, f ive distinguishing criteria were found to be essential for xenoestrogen act ivity, using E-2 as a template: (1) H-bonding ability of the phenolic ring mimicking the 3-OH, (2) H-bond donor mimicking the 17 beta -OH and O-O dist ance between 3- and 17 beta -OH, (3) precise steric hydrophobic centers mim icking steric 7 alpha- and 11 beta -substituents, (4) hydrophobicity, and ( 5) a ring structure. The S-position H-bonding ability of phenols is a signi ficant requirement for ER binding. This contributes as both a H-bond donor and acceptor, although predominantly as a donor. However, the 17 beta -OH c ontributes as a H-bond donor only. The precise space (the size and orientat ion) of steric hydrophobic bulk groups is as important as a 17 beta -OH. Wh ere a direct comparison can be made, strong estrogens tend to be more hydro phobic, A rigid ring structure favors ER binding. The knowledge derived fro m this study is rationalized into a set of hierarchical rules that will be useful in guidance for identification of potential estrogens.