Bisphenol AF: Halogen bonding effect is a major driving force for the dual ER-agonist and ER-antagonist activities

17 beta-Estradiol (E2) is a natural steroid ligand for the structurally and physiologically independent estrogen receptors (ERs) ER alpha and ER beta. We recently observed that CF3-containing bisphenol AF (BPAF) works as an agonist for ERa but as an antagonist for ER beta. Similar results were also observed for the CCl3-containing bisphenol designated as HPTE. Both BPAF and HPTE are comprised of a tri-halogenated methyl group in the central alkyl moiety of their bisphenol structures, which strongly suggests that halogens contribute directly to the agonist/antagonist dual biological functions. We conducted this study to investigate the structure-activity relationships by assessing together newly synthesized CF3- and CBr3-containing bisphenol E analogs (BPE-X). We first tested bisphenols for their receptor binding ability and then for their transcriptional activities. Halogen-containing bisphenols were found to be fully active for ER alpha, but almost completely inactive for ER beta. When we examined these bisphenols for their inhibitory activities for E2 in ER beta, we observed that they worked as distinct antagonists. The ascending order of agonist/antagonist dual biological functions was BPE-F < BPE-Cl (HPTE) <= BPAF < BPE-Br, demonstrating that the electrostatic halogen bonding effect is a major driving force of the bifunctional ER alpha agonist and ER beta antagonist activities of BPAF.