3-Vinylazetidin-2-Ones: Synthesis, antiproliferative and tubulin destabilizing activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

Shu Wang, Azizah M. Malebari, Thomas F. Greene, Niamh M. O’Boyle, Darren Fayne, Seema M. Nathwani, Brendan Twamley, Thomas McCabe, Niall O. Keely, Daniela M. Zisterer, Mary J. Meegan

Research output: Contribution to journalArticlepeer-review

Abstract

Microtubule-targeted drugs are essential chemotherapeutic agents for various types of cancer. A series of 3-vinyl-β-lactams (2-azetidinones) were designed, synthesized and evaluated as potential tubulin polymerization inhibitors, and for their antiproliferative effects in breast cancer cells. These compounds showed potent activity in MCF-7 breast cancer cells with an IC50 value of 8 nM for compound 7s 4-[3-Hydroxy-4-methoxyphenyl]-1-(3,4,5-trimethoxyphenyl)-3-vinylazetidin-2-one) which was comparable to the activity of Combretastatin A-4. Compound 7s had minimal cytotoxicity against both non-tumorigenic HEK-293T cells and murine mammary epithelial cells. The compounds inhibited the polymerisation of tubulin in vitro with an 8.7-fold reduction in tubulin polymerization at 10 μM for compound 7s and were shown to interact at the colchicine-binding site on tubulin, resulting in significant G2/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam 7s is targeting tubulin and resulted in mitotic catastrophe. A docking simulation indicated potential binding conformations for the 3-vinyl-β-lactam 7s in the colchicine domain of tubulin. These compounds are promising candidates for development as antiproiferative microtubule-disrupting agents.

Original languageEnglish
Article number56
JournalPharmaceuticals
Volume12
Issue number2
DOIs
Publication statusPublished - Jun 2019
Externally publishedYes

Keywords

  • 3-vinylazetidin-2-ones
  • Antimitotic
  • Antiproliferative activity
  • Combretastatin A-4
  • Tubulin
  • β-lactam

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