tamoxifen and thiazolyl-blue

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.

Topics: Apoptosis; beta-Lactams; Cell Division; Chemistry, Pharmaceutical; Computer Simulation; Estrogen Receptor alpha; Estrogen Receptor Antagonists; Estrogen Receptor beta; Estrogens; G2 Phase; Humans; Inhibitory Concentration 50; L-Lactate Dehydrogenase; Ligands; MCF-7 Cells; Models, Molecular; Myeloid Cell Leukemia Sequence 1 Protein; Protein Binding; Proto-Oncogene Proteins c-bcl-2; Software; Tetrazolium Salts; Thiazoles; Tubulin