2. Academic Validation
  3. Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

Antiproliferative and Tubulin-Destabilising Effects of 3-(Prop-1-en-2-yl)azetidin-2-Ones and Related Compounds in MCF-7 and MDA-MB-231 Breast Cancer Cells

  • Pharmaceuticals (Basel). 2023 Jul 13;16(7):1000. doi: 10.3390/ph16071000.
Shu Wang 1,  Azizah M Malebari 2,  Thomas F Greene 1,  Shubhangi Kandwal 3,  Darren Fayne 3,  Seema M Nathwani 4,  Daniela M Zisterer 4,  Brendan Twamley 5,  Niamh M O'Boyle 1,  Mary J Meegan 1
Affiliations

Affiliations

  • 1 School of Pharmacy and Pharmaceutical Sciences, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, Ireland.
  • 2 Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia.
  • 3 Molecular Design Group, School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, Ireland.
  • 4 School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, Ireland.
  • 5 School of Chemistry, Trinity College Dublin, Dublin 2, D02 PN40 Dublin, Ireland.
PMID: 37513912 DOI: 10.3390/ph16071000
Abstract

A series of novel 3-(prop-1-en-2-yl)azetidin-2-one, 3-allylazetidin-2-one and 3-(buta-1,3-dien-1-yl)azetidin-2-one analogues of combretastatin A-4 (CA-4) were designed and synthesised as colchicine-binding site inhibitors (CBSI) in which the ethylene bridge of CA-4 was replaced with a β-lactam (2-azetidinone) scaffold. These compounds, together with related prodrugs, were evaluated for their antiproliferative activity, cell cycle effects and ability to inhibit tubulin assembly. The compounds demonstrated significant in vitro antiproliferative activities in MCF-7 breast Cancer cells, particularly for compounds 9h, 9q, 9r, 10p, 10r and 11h, with IC50 values in the range 10-33 nM. These compounds were also potent in the triple-negative breast Cancer (TBNC) cell line MDA-MB-231, with IC50 values in the range 23-33 nM, and were comparable with the activity of CA-4. The compounds inhibited the polymerisation of tubulin in vitro, with significant reduction in tubulin polymerization, and were shown to interact at the colchicine-binding site on tubulin. Flow cytometry demonstrated that compound 9q arrested MCF-7 cells in the G2/M phase and resulted in cellular Apoptosis. The antimitotic properties of 9q in MCF-7 human breast Cancer cells were also evaluated, and the effect on the organization of microtubules in the cells after treatment with compound 9q was observed using confocal microscopy. The immunofluorescence results confirm that β-lactam 9q is targeting tubulin and resulted in mitotic catastrophe in MCF-7 cells. In silico molecular docking supports the hypothesis that the compounds interact with the colchicine-binding domain of tubulin. Compound 9q is a novel potent microtubule-destabilising agent with potential as a promising lead compound for the development of new antitumour agents.

Keywords

3-(buta-1,3-dien-1-yl)azetidin-2-ones; 3-(prop-1-en-2-yl)azetidin-2-one; 3-allylazetidin-2-ones; antimitotic; antiproliferative activity; combretastatin A-4; tubulin polymerization inhibitor; β-lactam.

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