Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4
Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-...
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MDPI AG
2021-10-01
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| author | Azizah M. Malebari Shu Wang Thomas F. Greene Niamh M. O’Boyle Darren Fayne Mohemmed Faraz Khan Seema M. Nathwani Brendan Twamley Thomas McCabe Daniela M. Zisterer Mary J. Meegan |
| author_facet | Azizah M. Malebari Shu Wang Thomas F. Greene Niamh M. O’Boyle Darren Fayne Mohemmed Faraz Khan Seema M. Nathwani Brendan Twamley Thomas McCabe Daniela M. Zisterer Mary J. Meegan |
| author_sort | Azizah M. Malebari |
| collection | DOAJ |
| description | Antimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound <b>10n</b> (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound <b>11n</b> (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC<sub>50</sub> values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound <b>10n</b> demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G<sub>2</sub>/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam <b>10n</b> caused a mitotic catastrophe by targeting tubulin. In addition, compound <b>10n</b> promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound <b>10n</b>, could be promising lead compounds for further clinical anti-cancer drug development. |
| first_indexed | 2024-03-10T05:10:03Z |
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| language | English |
| last_indexed | 2024-03-10T05:10:03Z |
| publishDate | 2021-10-01 |
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| spelling | doaj.art-7f2b0031e7fb41bc8378c9286946a1212023-11-23T00:55:31ZengMDPI AGPharmaceuticals1424-82472021-10-011411111910.3390/ph14111119Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4Azizah M. Malebari0Shu Wang1Thomas F. Greene2Niamh M. O’Boyle3Darren Fayne4Mohemmed Faraz Khan5Seema M. Nathwani6Brendan Twamley7Thomas McCabe8Daniela M. Zisterer9Mary J. Meegan10Department of Pharmaceutical Chemistry, College of Pharmacy, King Abdulaziz University, Jeddah 21589, Saudi ArabiaSchool of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandSchool of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandSchool of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandMolecular Design Group, School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandMolecular Design Group, School of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandSchool of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandSchool of Chemistry, Trinity College Dublin, 2 DO2R590 Dublin, IrelandSchool of Chemistry, Trinity College Dublin, 2 DO2R590 Dublin, IrelandSchool of Biochemistry and Immunology, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandSchool of Pharmacy and Pharmaceutical Sciences, Trinity College Dublin, Trinity Biomedical Sciences Institute, 152-160 Pearse Street, Dublin 2, DO2R590 Dublin, IrelandAntimitotic drugs that target tubulin are among the most widely used chemotherapeutic agents; however, the development of multidrug resistance has limited their clinical activity. We report the synthesis and biological properties of a series of novel 3-chloro-β-lactams and 3,3-dichloro-β-lactams (2-azetidinones) that are structurally related to the tubulin polymerisation inhibitor and vascular targeting agent, Combretastatin A-4. These compounds were evaluated as potential tubulin polymerisation inhibitors and for their antiproliferative effects in breast cancer cells. A number of the compounds showed potent activity in MCF-7 breast cancer cells, e.g., compound <b>10n</b> (3-chloro-4-(3-hydroxy-4-methoxy-phenyl)-1-(3,4,5-trimethoxyphenyl)azetidin-2-one) and compound <b>11n</b> (3,3-dichloro-4-(3-hydroxy-4-methoxyphenyl)-1-(3,4,5-trimethoxyphenyl)-azetidin-2-one), with IC<sub>50</sub> values of 17 and 31 nM, respectively, and displayed comparable cellular effects to those of Combretastatin A-4. Compound <b>10n</b> demonstrated minimal cytotoxicity against non-tumorigenic HEK-293T cells and inhibited the in vitro polymerisation of tubulin with significant G<sub>2</sub>/M phase cell cycle arrest. Immunofluorescence staining of MCF-7 cells confirmed that β-lactam <b>10n</b> caused a mitotic catastrophe by targeting tubulin. In addition, compound <b>10n</b> promoted apoptosis by regulating the expression of pro-apoptotic protein BAX and anti-apoptotic proteins Bcl-2 and Mcl-1. Molecular docking was used to explore the potential molecular interactions between novel 3-chloro-β-lactams and the amino acid residues of the colchicine binding active site cavity of β-tubulin. Collectively, these results suggest that 3-chloro-2-azetidinones, such as compound <b>10n</b>, could be promising lead compounds for further clinical anti-cancer drug development.https://www.mdpi.com/1424-8247/14/11/1119β-lactam3-chloroazetidin-2-onesantimitoticantiproliferative activitybreast cancertubulin polymerisation |
| spellingShingle | Azizah M. Malebari Shu Wang Thomas F. Greene Niamh M. O’Boyle Darren Fayne Mohemmed Faraz Khan Seema M. Nathwani Brendan Twamley Thomas McCabe Daniela M. Zisterer Mary J. Meegan Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 Pharmaceuticals β-lactam 3-chloroazetidin-2-ones antimitotic antiproliferative activity breast cancer tubulin polymerisation |
| title | Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 |
| title_full | Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 |
| title_fullStr | Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 |
| title_full_unstemmed | Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 |
| title_short | Synthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-4 |
| title_sort | synthesis and antiproliferative evaluation of 3 chloroazetidin 2 ones with antimitotic activity heterocyclic bridged analogues of combretastatin a 4 |
| topic | β-lactam 3-chloroazetidin-2-ones antimitotic antiproliferative activity breast cancer tubulin polymerisation |
| url | https://www.mdpi.com/1424-8247/14/11/1119 |
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