Bisphenol-C Is The Strongest Bifunctional Er Alpha-Agonist And Er Beta-Antagonist Due To Magnified Halogen Bonding

We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ER alpha but as an antagonist for ER beta. Similar results were observed for bisphenol E analogs (BPE-X) such as BPE-F, BPE-Cl, and BPE-Br, each consisting of a series of a tri-halogenated methyl group CX3 in the central alkyl moiety. It was demonstrated that the electrostatic halogen bond based on the dispersion force of halogen atoms is a major driving force in the activities of bifunctional ER alpha-agonist and ER beta-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a pi-pi conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ER alpha-agonist and ER beta-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ER alpha and ER beta in the luciferase reporter gene assay using HeLa cells. With high receptor-binding ability to both ERs, BPC was found to be fully active for ER alpha but inactive for ER beta. BPC's definite antagonist activity in ER beta was revealed by its inhibitory activity against 17 beta-estradiol. Thus, BPC is a bifunctional ER alpha-agonist and ER beta-antagonist. These agonist/antagonist activities were discovered to be extremely high among series of halogen-containing bisphenol compounds. This comparative structure-activity study revealed that the ascending order of ER alpha-agonist and ER beta-antagonist activities was BPE-F MUCH LESS-THAN BPE-Cl less than or similar to BPAF < BPE-Br MUCH LESS-THAN BPC. The highly intensified receptor interaction of BPC is attributable to the presence of an n-pi-pi-n conjugation system mediated through the >C = CCl2 double bond.