Document Type

Article

Rights

This item is available under a Creative Commons License for non-commercial use only

Disciplines

1. NATURAL SCIENCES, 1.4 CHEMICAL SCIENCES, Organic Chemistry, 1.6 BIOLOGICAL SCIENCES, Biochemistry and molecular biology

Publication Details

Journal of Medicinal Chemistry, 2014, Vol. 57, Issue 22, Pages 9370-9382

doi: http://dx.doi.org/10.1021/jm500670d

Abstract

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.

DOI

10.1021/jm500670d