Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones
The stilbene combretastatin A-4 (CA-4) is a potent microtubule-disrupting agent interacting at the colchicine-binding site of tubulin. In the present work, the synthesis, characterisation and mechanism of action of a series of 3-fluoro and 3,3-difluoro substituted β-lactams as analogues of the tubul...
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| Format: | Article |
| Language: | English |
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MDPI AG
2022-08-01
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| Series: | Pharmaceuticals |
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| Online Access: | https://www.mdpi.com/1424-8247/15/9/1044 |
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| author | Azizah M. Malebari Gabriela Duffy Morales Brendan Twamley Darren Fayne Mohemmed Faraz Khan Eavan C. McLoughlin Niamh M. O’Boyle Daniela M. Zisterer Mary J. Meegan |
| author_facet | Azizah M. Malebari Gabriela Duffy Morales Brendan Twamley Darren Fayne Mohemmed Faraz Khan Eavan C. McLoughlin Niamh M. O’Boyle Daniela M. Zisterer Mary J. Meegan |
| author_sort | Azizah M. Malebari |
| collection | DOAJ |
| description | The stilbene combretastatin A-4 (CA-4) is a potent microtubule-disrupting agent interacting at the colchicine-binding site of tubulin. In the present work, the synthesis, characterisation and mechanism of action of a series of 3-fluoro and 3,3-difluoro substituted β-lactams as analogues of the tubulin-targeting agent CA-4 are described. The synthesis was achieved by a convenient microwave-assisted Reformatsky reaction and is the first report of 3-fluoro and 3,3-difluoro β-lactams as CA-4 analogues. The β-lactam compounds 3-fluoro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxy phenyl)azetidin-2-one <b>32</b> and 3-fluoro-4-(3-fluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) <b>33</b> exhibited potent activity in MCF-7 human breast cancer cells with IC<sub>50</sub> values of 0.075 µM and 0.095 µM, respectively, and demonstrated low toxicity in non-cancerous cells. Compound <b>32</b> also demonstrated significant antiproliferative activity at nanomolar concentrations in the triple-negative breast cancer cell line Hs578T (IC<sub>50</sub> 0.033 μM), together with potency in the invasive isogenic subclone Hs578Ts(i)8 (IC<sub>50</sub> = 0.065 μM), while <b>33</b> was also effective in MDA-MB-231 cells (IC<sub>50</sub> 0.620 μM). Mechanistic studies demonstrated that <b>33</b> inhibited tubulin polymerisation, induced apoptosis in MCF-7 cells, and induced a downregulation in the expression of anti-apoptotic Bcl2 and survivin with corresponding upregulation in the expression of pro-apoptotic Bax. In silico studies indicated the interaction of the compounds with the colchicine-binding site, demonstrating the potential for further developing novel cancer therapeutics as microtubule-targeting agents. |
| first_indexed | 2024-03-09T22:52:39Z |
| format | Article |
| id | doaj.art-ce1244d0e8b94117b595145343d4558c |
| institution | Directory Open Access Journal |
| issn | 1424-8247 |
| language | English |
| last_indexed | 2024-03-09T22:52:39Z |
| publishDate | 2022-08-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Pharmaceuticals |
| spelling | doaj.art-ce1244d0e8b94117b595145343d4558c2023-11-23T18:17:32ZengMDPI AGPharmaceuticals1424-82472022-08-01159104410.3390/ph15091044Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-onesAzizah M. Malebari0Gabriela Duffy Morales1Brendan Twamley2Darren Fayne3Mohemmed Faraz Khan4Eavan C. McLoughlin5Niamh M. O’Boyle6Daniela M. Zisterer7Mary J. Meegan8Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaTrinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandSchool of Chemistry, Trinity College Dublin, Dublin 2, D02 PN40 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Biochemistry and Immunology, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandTrinity Biomedical Sciences Institute, School of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, 152-160 Pearse Street, Dublin 2, D02 R590 Dublin, IrelandThe stilbene combretastatin A-4 (CA-4) is a potent microtubule-disrupting agent interacting at the colchicine-binding site of tubulin. In the present work, the synthesis, characterisation and mechanism of action of a series of 3-fluoro and 3,3-difluoro substituted β-lactams as analogues of the tubulin-targeting agent CA-4 are described. The synthesis was achieved by a convenient microwave-assisted Reformatsky reaction and is the first report of 3-fluoro and 3,3-difluoro β-lactams as CA-4 analogues. The β-lactam compounds 3-fluoro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxy phenyl)azetidin-2-one <b>32</b> and 3-fluoro-4-(3-fluoro-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) <b>33</b> exhibited potent activity in MCF-7 human breast cancer cells with IC<sub>50</sub> values of 0.075 µM and 0.095 µM, respectively, and demonstrated low toxicity in non-cancerous cells. Compound <b>32</b> also demonstrated significant antiproliferative activity at nanomolar concentrations in the triple-negative breast cancer cell line Hs578T (IC<sub>50</sub> 0.033 μM), together with potency in the invasive isogenic subclone Hs578Ts(i)8 (IC<sub>50</sub> = 0.065 μM), while <b>33</b> was also effective in MDA-MB-231 cells (IC<sub>50</sub> 0.620 μM). Mechanistic studies demonstrated that <b>33</b> inhibited tubulin polymerisation, induced apoptosis in MCF-7 cells, and induced a downregulation in the expression of anti-apoptotic Bcl2 and survivin with corresponding upregulation in the expression of pro-apoptotic Bax. In silico studies indicated the interaction of the compounds with the colchicine-binding site, demonstrating the potential for further developing novel cancer therapeutics as microtubule-targeting agents.https://www.mdpi.com/1424-8247/15/9/1044combretastatin A-4antiproliferative activityfluorinated β-lactamsReformatsky reactioninhibition of tubulin polymerisationbreast cancer |
| spellingShingle | Azizah M. Malebari Gabriela Duffy Morales Brendan Twamley Darren Fayne Mohemmed Faraz Khan Eavan C. McLoughlin Niamh M. O’Boyle Daniela M. Zisterer Mary J. Meegan Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones Pharmaceuticals combretastatin A-4 antiproliferative activity fluorinated β-lactams Reformatsky reaction inhibition of tubulin polymerisation breast cancer |
| title | Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones |
| title_full | Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones |
| title_fullStr | Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones |
| title_full_unstemmed | Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones |
| title_short | Synthesis, Characterisation and Mechanism of Action of Anticancer 3-Fluoroazetidin-2-ones |
| title_sort | synthesis characterisation and mechanism of action of anticancer 3 fluoroazetidin 2 ones |
| topic | combretastatin A-4 antiproliferative activity fluorinated β-lactams Reformatsky reaction inhibition of tubulin polymerisation breast cancer |
| url | https://www.mdpi.com/1424-8247/15/9/1044 |
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