ERα-agonist and ERβ-antagonist bifunctional next-generation bisphenols with no halogens: BPAP, BPB, and BPZ.

Abstract As demonstrated for bisphenol AF (BPAF), the electrostatic halogen bond based on the London dispersion force of halogen atoms was found to be a major driving force of their bifunctional ERα-agonist and ERβ-antagonist activities. Because similar electronic effects are anticipated for hydrocarbon groups (alkyl or aryl groups), we hypothesized that bisphenol compounds consisting of such groups also work bifunctionally. In the present study, we examined bisphenol AP (BPAP), B (BPB), and Z (BPZ). After recognizing their considerably strong receptor binding affinities, we evaluated the abilities of BPAP, BPB, and BPZ to activate ERα and ERβ in a luciferase reporter gene assay. These bisphenols were fully active for ERα but completely inactive for ERβ. When we examined their inhibitory activities for 17β-estradiol in ERβ by two different qualitative and quantitative analytical methods, we found that those bisphenols worked as definite antagonists. Consequently, they were established as bifunctional ERα-agonists and ERβ-antagonists. The present structure − activity analyses revealed that the dispersion force works not only on the halogens but also on the hydrocarbon groups, and that it is a major driving force of bifunctional ERα-agonist and ERβ-antagonist activities.