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.
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Synthesis, Characterization, Molecular docking and Structure-Activity Relationships of Novel 2-Arylidene- and 2-Aminomethylenethiazolo[3,2-a]pyrimidines as Prospective Acetylcholinesterase InhibitorsNext Article in session
Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor (ER) Modulators and Downregulators with Subtype-Specific ERα and ERβ Activity
Published: 01 November 2017 by MDPI in 3rd International Electronic Conference on Medicinal Chemistry session Posters
Keywords: Estrogen receptor, antiproliferative, benzoxepin, acrylic acid