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

Abstract

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 selenophenecore 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 while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor. Add a New Element!Correspondence to: Jian Huang; Hai-Bing Zhou. ‡ These two authors contributed equally to this work Supporting information for this article is given via a link at the end of the document. HHS Public Access Author ManuscriptAuthor Manuscript Author Manuscript Author ManuscriptThis is the first report of selenophene-core compounds as ER ligands. In transcription assays, several selenophenes profiling as superagonists for ERα; moreover, a few selenophenes exhibited antiproliferative activity comparable to that of 4OHT in breast cancer MCF-7 cells while being nontoxic to normal VERO cells. These new ligands could act as models for the development of novel agents leading to improved therapeutics that target the estrogen receptor.

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