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Selenophenes: Introducing a New Element into the Core of Non-Steroidal Estrogen Receptor Ligands.
- Source :
-
ChemMedChem [ChemMedChem] 2017 Feb 03; Vol. 12 (3), pp. 235-249. Date of Electronic Publication: 2017 Jan 09. - Publication Year :
- 2017
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Abstract
- The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for the estrogen receptor (ER) has been well recognized. In this study we expanded the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship (SAR) analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene core and the nature of these substituents having a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2 f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most selenophenes were found to exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2 b), bis(4-fluoro-3-hydroxyphenyl)3-bromoselenophene (6 f), and 2,3,5-tris(hydroxyphenyl)thiophenes (8 b and 8 d) profiling as superagonists for ERα; however, several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8 c showing antiproliferative effects similar to that of 4-hydroxytamoxifen in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.<br /> (© 2017 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim.)
- Subjects :
- Animals
Binding Sites
Cell Proliferation drug effects
Chlorocebus aethiops
Estrogen Receptor alpha agonists
Estrogen Receptor alpha metabolism
Estrogen Receptor beta agonists
Estrogen Receptor beta metabolism
Humans
Ligands
MCF-7 Cells
Molecular Conformation
Molecular Docking Simulation
Organoselenium Compounds chemical synthesis
Organoselenium Compounds toxicity
Protein Binding
Protein Structure, Tertiary
Structure-Activity Relationship
Vero Cells
Estrogen Receptor alpha antagonists & inhibitors
Estrogen Receptor beta antagonists & inhibitors
Organoselenium Compounds chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1860-7187
- Volume :
- 12
- Issue :
- 3
- Database :
- MEDLINE
- Journal :
- ChemMedChem
- Publication Type :
- Academic Journal
- Accession number :
- 27976818
- Full Text :
- https://doi.org/10.1002/cmdc.201600593