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1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, 1.6 BIOLOGICAL SCIENCES, Biochemistry and molecular biology
Twelve novel β-lactams were synthesised and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ERα and ERβ, were determined. β-Lactams 23 and 26 had the strongest binding affinities for ERα (IC50 values: 40 and 8 nM respectively) and ERβ (IC50 values: 19 and 15 nM). β-Lactam 26 was the most potent in antiproliferative assays using MCF-7 breast cancer cells, and further biochemical analysis showed that it caused accumulation of cells in G2/M phase (mitotic blockade) and depolymerisation of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the pro-survival proteins Bcl-2 and Mcl-1. Computational modeling predicted binding preferences for the dual ER/tubulin ligand 26. This series is an important addition to the known pool of ER antagonists and β-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.
O'Boyle, N. (2014). β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand. Journal of Medicinal Chemistry, 2014, 57, 22, pp. 9370-9382 doi: http://dx.doi.org/10.1021/jm500670d
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