2. Academic Validation
  3. Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening

Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening

  • Bioorg Med Chem. 2020 Mar 1;28(5):115261. doi: 10.1016/j.bmc.2019.115261.
Miriam Carr 1,  Andrew J S Knox 2,  Daniel K Nevin 3,  Niamh O'Boyle 4,  Shu Wang 4,  Billy Egan 4,  Thomas McCabe 5,  Brendan Twamley 5,  Daniela M Zisterer 3,  David G Lloyd 3,  Mary J Meegan 4
Affiliations

Affiliations

  • 1 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland; School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland.
  • 2 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland; School of Biological and Health Sciences, Technology University Dublin, Dublin City Campus, Kevin St., Dublin 8 D08 NF82, Ireland. Electronic address: andrew.knox@tudublin.ie.
  • 3 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland.
  • 4 School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, 152 - 160 Pearse Street Trinity College Dublin, Dublin 2, Ireland.
  • 5 School of Chemistry, Trinity College Dublin, Dublin 2, Ireland.
PMID: 31987694 DOI: 10.1016/j.bmc.2019.115261
Abstract

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).

Keywords

4-Aryl-4H-chromene; Anti-proliferative; Anticancer; Benzopyran; Breast cancer; Cytotoxic; Estrogen receptor alpha; Estrogen receptor beta; Isoform selectivity; Knovenagel condensation; Molecular modeling; Subtype selectivity.

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