Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands. Issue 19 (1st October 2015)

• Record Type: Journal Article
• Authors: Ohta, Kiminori; Ogawa, Takumi; Oda, Akifumi; Kaise, Asako; Endo, Yasuyuki
• Is Part Of: Bioorganic & medicinal chemistry letters. Volume 25:Issue 19(2015)
• Page Start: 4174
• Page End: 4178
• Publication Date: 2015-10-01
• Subjects: Carborane -- Estrogen receptor -- Subtype selectivity -- Docking study; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; 572
• DOI: 10.1016/j.bmcl.2015.08.007
• Languages: English
• ISSNs: 0960-894X

Abstract

Graphical abstract: Abstract: Candidates for highly selective estrogen receptor-beta (ERβ) ligands (6a –c, 7a –c, 8a and8b ) were designed and synthesized based on carborane-containing ER ligands1 and2 as lead compounds. Among them, p -carboranylcyclohexanol derivatives8a and8b exhibited high ERβ selectivity in competitive binding assay: for example, 8a showed 56-fold selectivity for ERβ over ERα. Docking studies of8a and8b 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 in8a and8b appears to play a crucial role in the increased ERβ selectivity.