title: Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe.
abstract: The structure-activity relationships of antiproliferative β-lactams, focusing on modifications at the 4-position of the β-lactam ring, is described. Synthesis of this series of compounds was achieved utilizing the Staudinger and Reformatsky reactions. The antiproliferative activity was assessed in MCF-7 cells, where the 4-(4-ethoxy)phenyl substituted compound 26 displayed the most potent activity with an IC(50) value of 0.22 μM. The mechanism of action was demonstrated to be by inhibition of tubulin polymerisation. Cell exposure to combretastatin A-4 and 26 led to arrest of MCF-7 cells in the G2/M phase of the cell cycle and induction of apoptosis. Additionally, mitotic catastrophe for combretastatin A-4 and for 26 was demonstrated in breast cancer cells for the first time, as evidenced by the formation of giant, multinucleated cells.
authors.affiliation: School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland. oboyleni@tcd.ie
authors.forename: Niamh M
authors.initials: NM
authors.lastname: O'Boyle
authors.forename: Miriam
authors.initials: M
authors.lastname: Carr
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Greene
authors.forename: Niall O
authors.initials: NO
authors.lastname: Keely
authors.forename: Andrew J S
authors.initials: AJ
authors.lastname: Knox
authors.forename: Thomas
authors.initials: T
authors.lastname: McCabe
authors.forename: David G
authors.initials: DG
authors.lastname: Lloyd
authors.forename: Daniela M
authors.initials: DM
authors.lastname: Zisterer
authors.forename: Mary J
authors.initials: MJ
authors.lastname: Meegan
mesh_terms: D001384:Azetidines / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D018360:Crystallography, X-Ray; D005434:Flow Cytometry; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D018613:Microscopy, Confocal; D008856:Microscopy, Fluorescence; D008870:Microtubules / Q000187:drug effects*; D008938:Mitosis / Q000187:drug effects*; D008958:Models, Molecular; D013055:Spectrophotometry, Infrared
chemical_list: D001384:Azetidines; C082735:azetidine