Enhanced estrogen receptor beta (ERß) selectivity of fluorinated carborane-containing ER modulators.
Bioorg Med Chem Lett
; 23(24): 6555-8, 2013 Dec 15.
Article
em En
| MEDLINE
| ID: mdl-24268550
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/ß subtype selectivity. Here, we designed and synthesized a series of fluorinated carboranyl phenols as candidate ERß-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 ERß-binding affinity than the parent non-fluorinated compound 7. 1-Iodo-9-fluoro-m-carboranyl phenol 4f showed high ERß-binding affinity with an ERß/ERα selectivity ratio of 8.2. Among the compounds tested, 6 showed the highest ERß selectivity (10.1-fold) and the highest ER-agonistic activity (EC50 5.1×10(-10) M) in MCF-7 cell proliferation assay.
Palavras-chave
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Fenóis
/
Boranos
/
Compostos de Boro
/
Moduladores de Receptor Estrogênico
/
Receptor beta de Estrogênio
/
Flúor
Limite:
Humans
Idioma:
En
Revista:
Bioorg Med Chem Lett
Assunto da revista:
BIOQUIMICA
/
QUIMICA
Ano de publicação:
2013
Tipo de documento:
Article
País de afiliação:
Japão