Enhanced estrogen receptor beta (ERß) 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/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.