Optimisation of estrogen receptor subtype-selectivity of a 4-Aryl-4H-chromene scaffold previously identified by virtual screening. Issue 5 (1st March 2020)

• Record Type: Journal Article
• Authors: Carr, Miriam; Knox, Andrew J.S.; Nevin, Daniel K.; O'Boyle, Niamh; Wang, Shu; Egan, Billy; McCabe, Thomas; Twamley, Brendan; Zisterer, Daniela M.; Lloyd, David G.; Meegan, Mary J.
• Is Part Of: Bioorganic & medicinal chemistry. Volume 28:Issue 5(2020)
• Publication Date: 2020-03-01
• Subjects: Estrogen receptor alpha -- Estrogen receptor beta -- Isoform selectivity -- Subtype selectivity -- 4-Aryl-4H-chromene -- Benzopyran -- Anticancer -- Anti-proliferative -- Breast cancer -- Cytotoxic -- Knovenagel condensation -- Molecular modeling; EI Electron Impact -- ER Estrogen receptor -- GTP Guanidine triphosphate -- HRMS High Resolution Molecular Ion Determination -- IC Inhibitory concentration -- IR Infrared -- LDB Ligand binding domain -- LBP Ligand binding Pocket -- LRMS Low Resolution Mass Spectra -- MTD Maximum tolerated dose -- MTT 3-(4, 5-Dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide -- NMR Nuclear Magnetic Resonance -- ORTEP Oak Ridge Thermal Ellipsoid Plot -- PDB Protein Data Bank -- PBS Phosphate buffer saline -- SAR Structure-Activity Relationship -- SERM Selective Estrogen Receptor Modulation -- TBDMS tert-Butyldimethylchlorosilane -- THF Tetrahydrofuran -- TLC Thin Layer Chromatography -- TMCS Trimethylchlorosilane -- TMS Tetramethylsilane; Bioorganic chemistry -- Periodicals; Pharmaceutical chemistry -- Periodicals; Biochemistry -- Periodicals; Chemistry, Clinical -- Periodicals; Chemistry, Organic -- Periodicals; Chimie bio-organique -- Périodiques; Chimie pharmaceutique -- Périodiques; 615.19
• DOI: 10.1016/j.bmc.2019.115261
• Languages: English
• ISSNs: 0968-0896

Abstract

Graphical abstract: Abstract: 4-Aryl-4 H -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-4 H -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-4 H -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).