Thiophene-core estrogen receptor ligands having superagonist activity.

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 selective. Most of the bis(hydroxyphenyl)-thiophenes were ER beta selective, whereas the tris(hydroxyphenyl)-thiophenese were ER alpha 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.