Aliphatic Substitution of o-Carboranyl Phenols Enhances Estrogen Receptor Beta Selectivity

The two subtypes of estrogen receptor (ER), ER alpha and ER beta, differ greatly in expression pattern and biological functions, and ER beta-selective ligands candidates to treat immune-related disorders. ER beta-selective ligands have mostly been designed based the idea of introducing a substituent that interferes sterically with the ligand's interaction with Met421 to selectively decrease the affinity for ER alpha (the equivalent residue in ER beta is Ile373). Therefore, we designed and synthesized a series of carboranyl phenol derivatives bearing an aliphatic substituent as candidate ER beta-selective ligands. Introduction of a longer aliphatic substituent into the carboranyl moiety enhanced the ER beta selectivity of o-carboranyl phenol derivatives 4, but not m-carboranyl bisphenol derivatives 5. Compound 4c showed 7.4-fold ER beta selectivity in ER-binding assay and exhibited moderate estrogenic activity in cell proliferation assay using MCF-7 cell line.