Bisphenol-C is the strongest bifunctional ERα-agonist and ERβ-antagonist due to magnified halogen bonding.
Benzhydryl Compounds
/ chemistry
Binding, Competitive
/ drug effects
Estrogen Receptor alpha
/ agonists
Estrogen Receptor beta
/ antagonists & inhibitors
Genes, Reporter
Halogens
/ metabolism
HeLa Cells
Humans
Ligands
Luciferases
/ metabolism
Phenols
/ chemistry
Transcriptional Activation
/ drug effects
Journal
PloS one
ISSN: 1932-6203
Titre abrégé: PLoS One
Pays: United States
ID NLM: 101285081
Informations de publication
Date de publication:
2021
2021
Historique:
received:
22
10
2020
accepted:
07
01
2021
entrez:
9
2
2021
pubmed:
10
2
2021
medline:
8
9
2021
Statut:
epublish
Résumé
We reported that bisphenol AF (BPAF) works as an agonist for estrogen receptor (ER) ERα but as an antagonist for ERβ. 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 ERα-agonist and ERβ-antagonist. Since the chlorine atoms present in bisphenol C (BPC) exist in a π-π conjugated system due to the presence of an adjacent C = C double bond, we intended to prove that BPC is also a bifunctional ERα-agonist and ERβ-antagonist exhibiting greatly enhanced agonist/antagonist activities. BPC was evaluated for its ability to activate ERα and ERβ 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 ERα but inactive for ERβ. BPC's definite antagonist activity in ERβ was revealed by its inhibitory activity against 17β-estradiol. Thus, BPC is a bifunctional ERα-agonist and ERβ-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 ERα-agonist and ERβ-antagonist activities was BPE-F ≪ BPE-Cl ≲ BPAF < BPE-Br ≪ BPC. The highly intensified receptor interaction of BPC is attributable to the presence of an n-π-π-n conjugation system mediated through the >C = CCl2 double bond.
Identifiants
pubmed: 33561155
doi: 10.1371/journal.pone.0246583
pii: PONE-D-20-33235
pmc: PMC7872235
doi:
Substances chimiques
Benzhydryl Compounds
0
Estrogen Receptor alpha
0
Estrogen Receptor beta
0
Halogens
0
Ligands
0
Phenols
0
bisphenol C
98817I7XJ2
Luciferases
EC 1.13.12.-
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e0246583Déclaration de conflit d'intérêts
The authors declare that no competing interests exist.
Références
Bioorg Med Chem. 2020 Feb 1;28(3):115274
pubmed: 31879182
Endocr Rev. 2009 Feb;30(1):75-95
pubmed: 19074586
Physiol Rev. 2007 Jul;87(3):905-31
pubmed: 17615392
FEBS J. 2007 Dec;274(24):6340-51
pubmed: 18005256
Mol Endocrinol. 2002 Aug;16(8):1810-27
pubmed: 12145336
Chem Rev. 2016 Feb 24;116(4):2478-601
pubmed: 26812185
J Steroid Biochem Mol Biol. 2012 Jul;130(3-5):180-5
pubmed: 21414406
Endocrinology. 1999 Dec;140(12):5746-53
pubmed: 10579340
Sci Rep. 2017 Jun 14;7(1):3509
pubmed: 28615710
J Clin Endocrinol Metab. 2005 Mar;90(3):1830-44
pubmed: 15598686
J Mol Model. 2007 Feb;13(2):291-6
pubmed: 16927107
Anal Chim Acta. 2016 Feb 18;908:22-53
pubmed: 26826686
Toxicol Lett. 2006 Dec 1;167(2):95-105
pubmed: 17049190
Br J Pharmacol. 2008 Mar;153 Suppl 2:S1-209
pubmed: 18347570
Toxicology. 2006 Sep 21;226(2-3):79-89
pubmed: 16860916
J Biol Chem. 2015 May 8;290(19):12332-45
pubmed: 25805499
Environ Health Perspect. 2002 Dec;110 Suppl 6:925-9
pubmed: 12634121
BMC Cancer. 2018 May 30;18(1):607
pubmed: 29843638
Environ Health Perspect. 2010 Sep;118(9):1267-72
pubmed: 20427257
Fertil Steril. 2016 Sep 15;106(4):820-6
pubmed: 27504789
J Steroid Biochem Mol Biol. 2011 Oct;127(1-2):27-34
pubmed: 21605673
Curr Top Med Chem. 2012;12(6):486-504
pubmed: 22242852
Cell. 1995 Dec 15;83(6):835-9
pubmed: 8521507
Anal Biochem. 1976 May 7;72:248-54
pubmed: 942051
Endocr Rev. 2015 Dec;36(6):E1-E150
pubmed: 26544531
Biochem Biophys Res Commun. 1999 Jan 19;254(2):311-4
pubmed: 9918834
Environ Health Perspect. 2005 Aug;113(8):926-33
pubmed: 16079060
Trends Endocrinol Metab. 2002 Jul;13(5):220-5
pubmed: 12185669
Mol Cell. 2004 Feb 13;13(3):317-27
pubmed: 14967140
J Environ Public Health. 2012;2012:713696
pubmed: 22991565
Environ Health Perspect. 2008 Jan;116(1):32-8
pubmed: 18197296
Toxicol Appl Pharmacol. 2019 Aug 15;377:114610
pubmed: 31195007
Neuropharmacology. 1999 Mar;38(3):361-73
pubmed: 10219974
Pharmacol Rev. 2006 Dec;58(4):685-704
pubmed: 17132848
Br J Pharmacol Chemother. 1959 Mar;14(1):48-58
pubmed: 13651579
Proc Natl Acad Sci U S A. 2012 Sep 11;109(37):14930-5
pubmed: 22927406