Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening
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Biochemistry and molecular biology, Immunology
4-Aryl-4H-Chromene derivatives have been previously shown to exhibit anti-proliferative, apoptotic and anti-angiogenic activity in a variety of tumor models in vitro and in vivo generally via activation of caspases through inhibition of tubulin polymerisation. We have previously identified by Virtual Screening (VS) a 4-aryl-4H-chromene scaffold, of which two examples were shown to bind Estrogen Receptor α and β with low nanomolar affinity and <20-fold selectivity for α over β and low micromolar anti-proliferative activity in the MCF-7 cell line. Thus, using the 4-aryl-4H-chromene scaffold as a starting point, a series of compounds with a range of basic arylethers at C-4 and modifications at the C3-ester substituent of the benzopyran ring were synthesised, producing some potent ER antagonists in the MCF-7 cell line which were highly selective for ERα (compound 35; 350-fold selectivity) or ERβ (compound 42; 170-fold selectivity).
Miriam Carr, Andrew J.S. Knox, Daniel K. Nevin, Niamh O'Boyle, Shu Wang, Billy Egan, Thomas McCabe, Brendan Twamley, Daniela M. Zisterer, David G. Lloyd, Mary J. Meegan, Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening, Bioorganic & Medicinal Chemistry, Volume 28, Issue 5, 2020, 115261, ISSN 0968-0896, https://doi.org/10.1016/j.bmc.2019.115261.
Trinity College IITAC research initiative (HEA PRTLI); Enterprise Ireland (EI); Science Foundation Ireland (SFI); Wellcome Trust.
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Bioorganic & Medicinal Chemistry