Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands

Bioorg Med Chem Lett. 2015 Oct 1;25(19):4174-8. doi: 10.1016/j.bmcl.2015.08.007. Epub 2015 Aug 7.

Abstract

Candidates for highly selective estrogen receptor-beta (ERβ) ligands (6a-c, 7a-c, 8a and 8b) were designed and synthesized based on carborane-containing ER ligands 1 and 2 as lead compounds. Among them, p-carboranylcyclohexanol derivatives 8a and 8b exhibited high ERβ selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ERβ over ERα. Docking studies of 8a and 8b with the ERα and ERβ ligand-binding domains (LBDs) suggested that the p-carborane cage of the ligands is located close to key amino acid residues that influence ER-subtype selectivity, that is, Leu384 in the ERα LBD and Met336 in the ERβ LBD. The p-carborane cage in 8a and 8b appears to play a crucial role in the increased ERβ selectivity.

Keywords: Carborane; Docking study; Estrogen receptor; Subtype selectivity.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Boranes / chemical synthesis
  • Boranes / chemistry
  • Boranes / pharmacology*
  • Dose-Response Relationship, Drug
  • Drug Design*
  • Estrogen Receptor beta / antagonists & inhibitors*
  • Humans
  • Ligands
  • Molecular Dynamics Simulation
  • Molecular Structure
  • Structure-Activity Relationship

Substances

  • Boranes
  • Estrogen Receptor beta
  • Ligands