title: Design and synthesis of carborane-containing estrogen receptor-beta (ERβ)-selective ligands.
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.
authors: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: k-ohta@tohoku-pharm.ac.jp.
authors: Kiminori
authors: K
authors: Ohta
authors: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors: Takumi
authors: T
authors: Ogawa
authors: Faculty of Pharmacy, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, Ishikawa 920-1192, Japan.
authors: Akifumi
authors: A
authors: Oda
authors: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors: Asako
authors: A
authors: Kaise
authors: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan. Electronic address: yendo@tohoku-pharm.ac.jp.
authors: Yasuyuki
authors: Y
authors: Endo
mesh_terms: D001880:Boranes / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors*; D006801:Humans; D008024:Ligands; D056004:Molecular Dynamics Simulation; D015394:Molecular Structure; D013329:Structure-Activity Relationship
chemical_list: D001880:Boranes; D047629:Estrogen Receptor beta; D008024:Ligands
keywords: Carborane; Docking study; Estrogen receptor; Subtype selectivity