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Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity
* 1 , 2 , 1
1  School of Pharmacy and Pharmaceutical Sciences, University of Dublin, Trinity College, Dublin 2, Ireland
2  School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, University of Dublin, Trinity College, Dublin 2, Ireland

Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session Posters

Estrogen receptor a (ERa) is an important target for the design of drugs such as tamoxifen and fulvestrant. Three series of ER-ligands based on the benzoxepin scaffold structure were synthesised – series I containing an acrylic acid, series II with an acrylamide and series III with a saturated carboxylic acid substituent. These compounds were shown to be high affinity ligands for the ER with nanomolar IC50 binding values. Series I acrylic acid ligands were generally ERa selective. In particular, a compound (1) featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ERa and ERb expression in MCF-7 breast cancer cells. Interestingly, from series III, a phenoxybutyric acid derivative compound (2) was not antiproliferative and selectively downregulated ERb. A docking study of the benzoxepin ligands was undertaken. Compound 1 is a promising lead for development as a clinically relevant SERD, whilst compound 2 will be a useful experimental probe for helping to elucidate the role of ERβ in cancer cells.

Keywords: Estrogen receptor, antiproliferative, benzoxepin, acrylic acid