2. Academic Validation
  3. Bisphenol AF: Halogen bonding effect is a major driving force for the dual ERα-agonist and ERβ-antagonist activities

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

  • Bioorg Med Chem. 2020 Feb 1;28(3):115274. doi: 10.1016/j.bmc.2019.115274.
Xiaohui Liu 1,  Keitaro Suyama 1,  Junichi Shiki 1,  Kohei Torikai 1,  Takeru Nose 1,  Miki Shimohigashi 2,  Yasuyuki Shimohigashi 3
Affiliations

Affiliations

  • 1 Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Motooka 744, Nishi-ku, Fukuoka 819-0395, Japan.
  • 2 Division of Biology, Department of Earth System of Science, Faculty of Science, Fukuoka University, Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan; Risk Science Research Institute, Ikimatsudai 3-7-5, Nishi-ku, Fukuoka 819-0044, Japan.
  • 3 Department of Chemistry, Faculty and Graduate School of Sciences, Kyushu University, Motooka 744, Nishi-ku, Fukuoka 819-0395, Japan; Risk Science Research Institute, Ikimatsudai 3-7-5, Nishi-ku, Fukuoka 819-0044, Japan. Electronic address: shimo@kyudai.jp.
PMID: 31879182 DOI: 10.1016/j.bmc.2019.115274
Abstract

17β-Estradiol (E2) is a natural steroid ligand for the structurally and physiologically independent estrogen receptors (ERs) ERα and ERβ. We recently observed that CF3-containing bisphenol AF (BPAF) works as an agonist for ERα but as an antagonist for ERβ. 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 ERα, but almost completely inactive for ERβ. When we examined these bisphenols for their inhibitory activities for E2 in ERβ, 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 ERα Agonist and ERβ Antagonist activities of BPAF.

Keywords

Agonist; Antagonist; Bisphenol; Estrogen receptor; Halogen bonding; Structure-activity relationship.

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