Synthesis, biochemical and molecular modelling studies of antiproliferative azetidinones causing microtubule disruption and mitotic catastrophe

Niamh M. O'Boyle, Miriam Carr, Lisa M. Greene, Niall O. Keely, Andrew J.S. Knox, Thomas McCabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Research output: Contribution to journalArticlepeer-review

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.

Original languageEnglish
Pages (from-to)4595-4607
Number of pages13
JournalEuropean Journal of Medicinal Chemistry
Volume46
Issue number9
DOIs
Publication statusPublished - Sep 2011
Externally publishedYes

Keywords

  • Antiproliferative
  • Azetidinone
  • Combretastatin
  • Mitotic catastrophe
  • Tubulin
  • β-lactam

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