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Pharmaceuticals 2019, 12(2), 56; https://doi.org/10.3390/ph12020056

3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells

1
School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, 2 DO2R590 Dublin, Ireland
2
Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi Arabia
3
School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, 2 DO2R590 Dublin, Ireland
4
School of Chemistry, Trinity College Dublin, 2 DO2R590 Dublin, Ireland
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Received: 1 March 2019 / Revised: 2 April 2019 / Accepted: 7 April 2019 / Published: 11 April 2019
(This article belongs to the Special Issue Anticancer Drugs)
PDF [2817 KB, uploaded 11 April 2019]
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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 M 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.
Keywords: Combretastatin A-4; β-lactam; 3-vinylazetidin-2-ones; antiproliferative activity; tubulin; antimitotic. Combretastatin A-4; β-lactam; 3-vinylazetidin-2-ones; antiproliferative activity; tubulin; antimitotic.
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).
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Wang, S.; Malebari, A.M.; Greene, T.F.; O’Boyle, N.M.; Fayne, D.; Nathwani, S.M.; Twamley, B.; McCabe, T.; Keely, N.O.; Zisterer, D.M.; Meegan, M.J. 3-Vinylazetidin-2-Ones: Synthesis, Antiproliferative and Tubulin Destabilizing Activity in MCF-7 and MDA-MB-231 Breast Cancer Cells. Pharmaceuticals 2019, 12, 56.

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