Thiophene-core estrogen receptor ligands having superagonist activity

Jian Min, Pengcheng Wang, Sathish Srinivasan, Jerome C. Nwachukwu, Pu Guo, Minjian Huang, Kathryn E. Carlson, John A. Katzenellenbogen, Kendall W. Nettles, Hai Bing Zhou

Research output: Contribution to journalArticlepeer-review


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.

Original languageEnglish (US)
Pages (from-to)3346-3366
Number of pages21
JournalJournal of Medicinal Chemistry
Issue number8
StatePublished - Apr 25 2013

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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