title: β-Lactam estrogen receptor antagonists and a dual-targeting estrogen receptor/tubulin ligand.
abstract: 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.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology and ‡School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College , 152-160 Pearse Street, Dublin 2, Ireland.
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.forename: Jade K
authors.initials: JK
authors.lastname: Pollock
authors.forename: Miriam
authors.initials: M
authors.lastname: Carr
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Knox
authors.forename: Seema M
authors.initials: SM
authors.lastname: Nathwani
authors.forename: Shu
authors.initials: S
authors.lastname: Wang
authors.forename: Laura
authors.initials: L
authors.lastname: Caboni
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D017209:Apoptosis; D002455:Cell Division; D002626:Chemistry, Pharmaceutical / Q000379:methods; D003198:Computer Simulation; D065171:Estrogen Receptor Antagonists / Q000737:chemistry*; D047628:Estrogen Receptor alpha / Q000037:antagonists & inhibitors / Q000737:chemistry; D047629:Estrogen Receptor beta / Q000037:antagonists & inhibitors / Q000737:chemistry; D004967:Estrogens / Q000737:chemistry; D016195:G2 Phase; D006801:Humans; D020128:Inhibitory Concentration 50; D007770:L-Lactate Dehydrogenase / Q000737:chemistry; D008024:Ligands; D061986:MCF-7 Cells; D008958:Models, Molecular; D064549:Myeloid Cell Leukemia Sequence 1 Protein / Q000737:chemistry; D011485:Protein Binding; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000737:chemistry; D012984:Software; D013778:Tetrazolium Salts / Q000737:chemistry; D013844:Thiazoles / Q000737:chemistry; D014404:Tubulin / Q000737:chemistry*; D047090:beta-Lactams / Q000737:chemistry*
chemical_list: C506487:ESR1 protein, human; D065171:Estrogen Receptor Antagonists; D047628:Estrogen Receptor alpha; D047629:Estrogen Receptor beta; D004967:Estrogens; D008024:Ligands; C579095:MCL1 protein, human; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D013778:Tetrazolium Salts; D013844:Thiazoles; D014404:Tubulin; D047090:beta-Lactams; D007770:L-Lactate Dehydrogenase; C022616:thiazolyl blue