Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe
Files
(Published version)
Date
2011
Authors
O'Boyle, N.M.
Carr, M.
Greene, L.M.
Keely, N.O.
Knox, A.J.S.
McCabe, T.
Lloyd, D.G.
Zisterer, D.M.
Meegan, M.J.
Editors
Advisors
Journal Title
Journal ISSN
Volume Title
Type:
Journal article
Citation
European Journal of Medicinal Chemistry, 2011; 46(9):4595-4607
Statement of Responsibility
Conference Name
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 IC50 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.
School/Discipline
Dissertation Note
Provenance
Description
Access Status
Rights
Copyright 2011 Elsevier Masson SAS
Access Condition Notes: Post print is available