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

Xiaohui Liu, Keitaro Suyama, Junichi Shiki, Kohei Torikai, Takeru Nose, Miki Shimohigashi, Yasuyuki Shimohigashi

Research output: Contribution to journalArticle

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.

Original languageEnglish
Article number115274
JournalBioorganic and Medicinal Chemistry
Volume28
Issue number3
DOIs
Publication statusPublished - Feb 1 2020

Fingerprint

Halogens
Estrogen Receptors
Estrogens
Structure-Activity Relationship
Estrogen Receptor Antagonists
4,4'-hexafluorisopropylidene diphenol
Static Electricity
Electrostatics
Estradiol
Steroids
Ligands

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Molecular Medicine
  • Molecular Biology
  • Pharmaceutical Science
  • Drug Discovery
  • Clinical Biochemistry
  • Organic Chemistry

Cite this

Bisphenol AF : Halogen bonding effect is a major driving force for the dual ERα-agonist and ERβ-antagonist activities. / Liu, Xiaohui; Suyama, Keitaro; Shiki, Junichi; Torikai, Kohei; Nose, Takeru; Shimohigashi, Miki; Shimohigashi, Yasuyuki.

In: Bioorganic and Medicinal Chemistry, Vol. 28, No. 3, 115274, 01.02.2020.

Research output: Contribution to journalArticle

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