Development of subtype-selective estrogen receptor modulators using the bis(4-hydroxyphenyl)silanol core as a stable isostere of bis(4-hydroxyphenyl)methanol.

Abstract

In this study, we synthesized and evaluated silanol-based bisphenol derivatives as stable isosteres of bis(4-hydroxyphenyl)methanol. The developed silanols exhibited estrogen receptor (ER)-modulating activity. Among them, bis(4-hydroxyphenyl)(methyl)silanol (5a) showed a characteristic ER subtype selectivity, namely, antagonistic activity toward ERα and agonistic activity toward ERβ. Docking simulation indicated that the silanol moiety plays a key role in this selectivity. Our results suggest that silanol-based bisphenols offer a unique scaffold for biologically active compounds.