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Thiophene-core estrogen receptor ligands having superagonist activity

Academic Article
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Overview

authors

  • Min, J.
  • Wang, P. C.
  • Srinivasan, S.
  • Nwachukw, J. C.
  • Guo, P.
  • Huang, M. J.
  • Carlson, K. E.
  • Katzenellenbogen, J. A.
  • Nettles, Kendall
  • Zhou, H. B.

publication date

  • April 2013

journal

  • Journal of Medicinal Chemistry  Journal

abstract

  • To probe the importance of the heterocyclic core of estrogen receptor (ER) ligands, we prepared a series of thiophene-core ligands by Suzuki cross-coupling of aryl boronic acids with bromo-thiophenes and we assessed their receptor binding and cell biological activities. The disposition of the phenol substituents on the thiophene core, at alternate or adjacent sites, and the nature of substituents on these phenols, all contribute to binding affinity and subtype selectivity. Most of the bis(hydroxyphenyl)-thiophenes were ERβ selective, whereas the tris(hydroxyphenyl)-thiophenes were ERα selective; analogous furan-core compounds generally have lower affinity and less selectivity. Some diarylthiophenes show distinct superagonist activity in reporter gene assays, giving maximal activities 2-3 times that of estradiol, and modeling suggests that these ligands have a different interaction with a hydrogen-bonding residue in helix-11. Ligand-core modification may be a new strategy for developing ER ligands whose selectivity is based on having transcriptional activity greater than that of estradiol.

subject areas

  • Estrogen Receptor alpha
  • Estrogen Receptor beta
  • Hydrogen Bonding
  • Ligands
  • Structure-Activity Relationship
  • Thiophenes
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Identity

PubMed Central ID

  • PMC3666579

International Standard Serial Number (ISSN)

  • 0022-2623

Digital Object Identifier (DOI)

  • 10.1021/jm400157e

PubMed ID

  • 23586645
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Additional Document Info

start page

  • 3346

end page

  • 3366

volume

  • 56

issue

  • 8

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