Selenophenes: Introducing a New Element into the Core of Non‐Steroidal Estrogen Receptor Ligands

The importance of the heterocyclic core elements with peripheral phenolic and alkyl substituents as a dominant structural motif of ligands for estrogen receptor (ER) has been well recognized. Here, we expand the structural diversity of core elements by preparing selenium-containing heterocycles and exploring the activities of these selenophenes on the two ERs, ERα and ERβ. Careful structure-activity relationship analysis of their ER binding affinities showed that most selenophenes are ERβ-selective, with the position of the phenol substituents on the selenophene-core and the nature of these substituents having in a marked effect on their binding affinities. The compound bis(2-fluoro-4-hydroxyphenyl)selenophene (2f) has the highest relative binding affinity (RBA) of 24.3 for ERβ. In transcription assays, most of selenophenes exhibit partial to full agonist activity for both ER subtypes, with compounds bis(2-methyl-4-hydroxyphenyl)selenophene (2b), bis(4-fluoro-3-hydroxyphenyl) 3-bromoselenophene (6f), 2,3,5-tris(hydroxyphenyl)-thiophenes (8b and 8d) profiling as superagonists for ERα, but several compounds display a range of ERα or ERβ antagonistic activities. A few selenophenes exhibited antiproliferative activity, with compound 8c showing antiproliferative effects comparable to that of 4OHT in breast cancer MCF-7 cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.