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

Candidates for highly selective estrogen receptor-beta (ERb) 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 ERb selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ER beta over ER alpha. Docking studies of 8a and 8b with the ERa and ERb 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 ER alpha LBD and Met336 in the ERb LBD. The p-carborane cage in 8a and 8b appears to play a crucial role in the increased ERb selectivity. (C) 2015 Elsevier Ltd. All rights reserved.