Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones

Niamh M. O'Boyle, Lisa M. Greene, Orla Bergin, Jean Baptiste Fichet, Thomas McCabe, David G. Lloyd, Daniela M. Zisterer, Mary J. Meegan

Research output: Contribution to journalArticlepeer-review

Abstract

A series of azetidin-2-ones substituted at positions 1, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin-binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerisation that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC50 values of 7 nM and 10 nM, respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example, 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC50 = 1.37 μM) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) β-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs.

Original languageEnglish
Pages (from-to)2306-2325
Number of pages20
JournalBioorganic and Medicinal Chemistry
Volume19
Issue number7
DOIs
Publication statusPublished - 1 Apr 2011
Externally publishedYes

Keywords

  • Antiproliferative
  • Azetidinone
  • Colchicine
  • Combretastatin A-4 analogues
  • Cytotoxicity
  • Reformatsky reaction
  • Staudinger reaction
  • Structure-activity
  • Tubulin
  • β-Lactam

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