Lead Optimization of Benzoxepin-Type Selective Estrogen Receptor Modulators and Downregulators with Subtype-Specific ER[alpha] and ER[beta] Activity

Estrogen receptor [alpha] (ER[alpha]) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). 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 wi...

Full description

Saved in:
Bibliographic Details
Published in:Journal of the Statistical and Social Inquiry Society of Ireland 2018-01, Vol.47, p.1
Main Authors: O'Boyle, Niamh M, Barrett, Irene, Greene, Lisa M, Carr, Miriam, Fayne, Darren, Twamley, Brendan, Knox, Andrew J.S, Keely, Niall O, Zisterer, Daniela M, Meegan, Mary J
Format: Article
Language:English
Subjects:
Acrylic acid
Amides
Estrogens
Fulvestrant
Phenols (Class of compounds)
Tamoxifen
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary:Estrogen receptor [alpha] (ER[alpha]) is an important target for the design of drugs such as tamoxifen (2a) and fulvestrant (5). 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 I[C.sub.50] binding values. Series I acrylic acid ligands were generally ER[alpha] selective. In particular, compound 13e featuring a phenylpenta-2,4-dienoic acid substituent was shown to be antiproliferative and downregulated ER[alpha] and ER[beta] expression in MCF-7 breast cancer cells. Interestingly, from series III, the phenoxybutyric acid derivative compound 22 was not antiproliferative and selectively downregulated ER[beta]. A docking study of the benzoxepin ligands was undertaken. Compound 13e is a promising lead for development as a clinically relevant SERD, whilst compound 22 will be a useful experimental probe for helping to elucidate the role of ER[beta] in cancer cells.
ISSN:0081-4776
DOI:10.1021/acs.jmedchem.6b01917