Synthesis of substituted oxabicyclic phenol derivatives with increased affinity and activity for the classical estrogen receptor ERα

The classical estrogen receptor (ER) plays a crucial role in health and disease, acting as a receptor for its endogenous ligand 17β-estradiol (E2). Like its counterpart ERβ, ER can bind a wide range of natural and synthetic small molecules. Extensive screening efforts have led to the discovery of various ER agonists, many of which are based on the oxabicyclo[3.3.1]-nonene scaffold. One such compound, AB-1, was the focus of a detailed investigation.

The study details the synthesis of a series of analogs derived from the AB-1 scaffold, with the aim of enhancing their binding affinity to the ER and improving their functional potencies in ER-mediated assays. Among these analogs, compound 9 stands out for its remarkable properties. Compound 9 exhibits subnanomolar potencies for ER binding, with an IC50 value of just 0.45 nM.

This potency also extends to ER-dependent transcription, with an EC50 of 0.37 nM, and ER-mediated cell proliferation, with an EC50 of 0.03 nM. Such high potencies are remarkably close to those of the endogenous ligand E2, indicating that compound 9 could be a promising scaffold for the development of new ER-targeted therapeutics.