title: Enhanced estrogen receptor beta (ERβ) selectivity of fluorinated carborane-containing ER modulators.
abstract: We previously showed that fluorination of the carborane-containing selective estrogen receptor modulator (SERM) BE360 altered the agonist/antagonist activity balance and the estrogen receptor (ER) α/β subtype selectivity. Here, we designed and synthesized a series of fluorinated carboranyl phenols as candidate ERβ-selective ligands. Introduction of a fluorine atom onto the carborane cage commonly reduced the binding affinity for ERα, to an extent that depended on the other substituents present. The B-fluorinated m-carboranyl phenol 4a showed fourfold more potent ERβ-binding affinity than the parent non-fluorinated compound 7. 1-Iodo-9-fluoro-m-carboranyl phenol 4f showed high ERβ-binding affinity with an ERβ/ERα selectivity ratio of 8.2. Among the compounds tested, 6 showed the highest ERβ selectivity (10.1-fold) and the highest ER-agonistic activity (EC50: 5.1×10(-10) M) in MCF-7 cell proliferation assay.
authors.affiliation: Faculty of Pharmaceutical Sciences, Tohoku Pharmaceutical University, 4-4-1 Komatsushima, Aoba-ku, Sendai 981-8558, Japan.
authors.forename: Kiminori
authors.initials: K
authors.lastname: Ohta
authors.forename: Takumi
authors.initials: T
authors.lastname: Ogawa
authors.forename: Asako
authors.initials: A
authors.lastname: Kaise
authors.forename: Yasuyuki
authors.initials: Y
authors.lastname: Endo
mesh_terms: D001880:Boranes / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D001896:Boron Compounds / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D049109:Cell Proliferation / Q000187:drug effects; D020847:Estrogen Receptor Modulators / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D047628:Estrogen Receptor alpha / Q000819:agonists / Q000037:antagonists & inhibitors / Q000378:metabolism; D047629:Estrogen Receptor beta / Q000819:agonists / Q000037:antagonists & inhibitors* / Q000378:metabolism; D005461:Fluorine / Q000737:chemistry*; D054879:Halogenation; D006801:Humans; D061986:MCF-7 Cells; D010636:Phenols / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D011485:Protein Binding
chemical_list: D001880:Boranes; D001896:Boron Compounds; D020847:Estrogen Receptor Modulators; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D010636:Phenols; D005461:Fluorine
keywords: Carborane; Estrogen receptor; Fluorine; Subtype selectivity