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-...
Guardado en:
| Autores principales: | , , , , , , , , , , |
|---|---|
| Formato: | article |
| Lenguaje: | EN |
| Publicado: |
MDPI AG
2021
|
| Materias: | |
| Acceso en línea: | https://doaj.org/article/7f2b0031e7fb41bc8378c9286946a121 |
| Etiquetas: |
Agregar Etiqueta
Sin Etiquetas, Sea el primero en etiquetar este registro!
|
| id |
oai:doaj.org-article:7f2b0031e7fb41bc8378c9286946a121 |
|---|---|
| record_format |
dspace |
| spelling |
oai:doaj.org-article:7f2b0031e7fb41bc8378c9286946a1212021-11-25T18:39:30ZSynthesis and Antiproliferative Evaluation of 3-Chloroazetidin-2-ones with Antimitotic Activity: Heterocyclic Bridged Analogues of Combretastatin A-410.3390/ph141111191424-8247https://doaj.org/article/7f2b0031e7fb41bc8378c9286946a1212021-10-01T00:00:00Zhttps://www.mdpi.com/1424-8247/14/11/1119https://doaj.org/toc/1424-8247Antimitotic 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.Azizah M. MalebariShu WangThomas F. GreeneNiamh M. O’BoyleDarren FayneMohemmed Faraz KhanSeema M. NathwaniBrendan TwamleyThomas McCabeDaniela M. ZistererMary J. MeeganMDPI AGarticleβ-lactam3-chloroazetidin-2-onesantimitoticantiproliferative activitybreast cancertubulin polymerisationMedicineRPharmacy and materia medicaRS1-441ENPharmaceuticals, Vol 14, Iss 1119, p 1119 (2021) |
| institution |
DOAJ |
| collection |
DOAJ |
| language |
EN |
| topic |
β-lactam 3-chloroazetidin-2-ones antimitotic antiproliferative activity breast cancer tubulin polymerisation Medicine R Pharmacy and materia medica RS1-441 |
| spellingShingle |
β-lactam 3-chloroazetidin-2-ones antimitotic antiproliferative activity breast cancer tubulin polymerisation Medicine R Pharmacy and materia medica RS1-441 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 |
| 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. |
| format |
article |
| 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 |
| title |
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_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_sort |
synthesis and antiproliferative evaluation of 3-chloroazetidin-2-ones with antimitotic activity: heterocyclic bridged analogues of combretastatin a-4 |
| publisher |
MDPI AG |
| publishDate |
2021 |
| url |
https://doaj.org/article/7f2b0031e7fb41bc8378c9286946a121 |
| work_keys_str_mv |
AT azizahmmalebari synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT shuwang synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT thomasfgreene synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT niamhmoboyle synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT darrenfayne synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT mohemmedfarazkhan synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT seemamnathwani synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT brendantwamley synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT thomasmccabe synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT danielamzisterer synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 AT maryjmeegan synthesisandantiproliferativeevaluationof3chloroazetidin2oneswithantimitoticactivityheterocyclicbridgedanaloguesofcombretastatina4 |
| _version_ |
1718410845114859520 |