TY - JOUR
T1 - Bisphenol AF
T2 - Halogen bonding effect is a major driving force for the dual ERα-agonist and ERβ-antagonist activities
AU - Liu, Xiaohui
AU - Suyama, Keitaro
AU - Shiki, Junichi
AU - Torikai, Kohei
AU - Nose, Takeru
AU - Shimohigashi, Miki
AU - Shimohigashi, Yasuyuki
N1 - Funding Information:
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI; grant nos. JP25740024, JP15K00557 and 19K12340 (to X.L.) and JP22221005 and JP15H01741 (to Y.S.). This work was also supported in part by a Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labor, and Welfare of Japan, under the contract/grant no. H20-Chemistry-General-003 (to Y.S.).
Funding Information:
This work was supported by the Japan Society for the Promotion of Science (JSPS) KAKENHI; grant nos. JP25740024 , JP15K00557 and 19K12340 (to X.L.) and JP22221005 and JP15H01741 (to Y.S.). This work was also supported in part by a Health and Labour Sciences Research Grant for Research on the Risk of Chemical Substances from the Ministry of Health, Labor, and Welfare of Japan , under the contract/grant no. H20-Chemistry-General-003 (to Y.S.).
Publisher Copyright:
© 2019 Elsevier Ltd
PY - 2020/2/1
Y1 - 2020/2/1
N2 - 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.
AB - 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.
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U2 - 10.1016/j.bmc.2019.115274
DO - 10.1016/j.bmc.2019.115274
M3 - Article
C2 - 31879182
AN - SCOPUS:85077169485
SN - 0968-0896
VL - 28
JO - Bioorganic and Medicinal Chemistry
JF - Bioorganic and Medicinal Chemistry
IS - 3
M1 - 115274
ER -