β‑Lactam Estrogen Receptor Antagonists and a Dual-Targeting Estrogen Receptor/Tubulin Ligand

Twelve
novel β-lactams were synthesized 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 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 β-lactam 26 is the first reported compound
that has dual-targeting properties for both the ER and tubulin.