β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.

Twelve novel beta-lactams were synthesized and their antiproliferative effects and binding affinity for the predominant isoforms of the estrogen receptor (ER), ER alpha and ER beta, were determined. beta-Lactams 23 and 26 had the strongest binding affinities for ER alpha (IC50 values: 40 and 8 nM, respectively) and ER beta (IC50 values: 19 and 15 nM). beta-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 G(2)/M phase (mitotic blockade) and depolymerization of tubulin in MCF-7 cells. Compound 26 also induced apoptosis and downregulation of the expression of 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 beta-lactam 26 is the first reported compound that has dual-targeting properties for both the ER and tubulin.