Dependence of estrogenic activity on the shape of the 4-alkyl substituent in simple phenols

The ability of certain chemicals to mimic the effects of natural steroid ho rmones and their potential to disrupt the delicate balance of the endocrine system in animals has attracted much interest in recent years. Alkylphenol ic chemicals have been reported to be weakly estrogenic, Estrogen receptor (ER) binding is primarily the result of interaction of the receptor with bo th a phenolic residue, and a hydrophobic pharmacophore, We have prepared an d screened various phenols having a bulky 4-alkyl group, which may interact hydrophobically with the receptor, for estrogenic activity by using a prev iously described reporter gene assay employing COS-1 cells transfected with rat ER alpha-expression plasmid and an appropriate reporter plasmid, Some of the tested compounds, such as 4-(1-adamantyl)phenol and 4-cycloalkylphen ols, exhibited much more potent activity than the typical estrogenic alkylp henol, 4-tert-octylphenol.