dc.contributor.author | Zisterer, Daniela | |
dc.date.accessioned | 2019-08-13T16:09:10Z | |
dc.date.available | 2019-08-13T16:09:10Z | |
dc.date.issued | 2019 | |
dc.date.submitted | 2019 | en |
dc.identifier.citation | Wang, S. and Malebari, A.M. and Greene, T.F. and O'Boyle, N.M. and Fayne, D. and Nathwani, S.M. and Twamley, B. and McCabe, T. and Keely, N.O. and Zisterer, D.M. and Meegan, M.J., 3-Vinylazetidin-2-Ones: Synthesis, antiproliferative and tubulin destabilizing activity in MCF-7 and MDA-MB-231 Breast Cancer Cells, Pharmaceuticals, 12, 2, 2019 | en |
dc.identifier.other | Y | |
dc.identifier.uri | http://hdl.handle.net/2262/89185 | |
dc.description.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 μM 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. | en |
dc.language.iso | en | en |
dc.publisher | MDPI | en |
dc.relation.ispartofseries | Pharmaceuticals; | |
dc.relation.ispartofseries | 12; | |
dc.relation.ispartofseries | 2; | |
dc.rights | Y | en |
dc.subject | Microtubule-targeted drugs | en |
dc.subject | Combretastatin A-4 | en |
dc.subject | β-lactam | en |
dc.subject | 3-vinylazetidin-2-ones | en |
dc.subject | Antiproliferative activity | en |
dc.subject | Tubulin | en |
dc.subject | Antimitotic | en |
dc.subject.lcsh | Microtubule-targeted drugs | en |
dc.title | 3-Vinylazetidin-2-Ones: Synthesis, antiproliferative and tubulin destabilizing activity in MCF-7 and MDA-MB-231 Breast Cancer Cells | en |
dc.type | Journal Article | en |
dc.type.supercollection | scholarly_publications | en |
dc.type.supercollection | refereed_publications | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/dzistrer | |
dc.identifier.rssinternalid | 206067 | |
dc.identifier.doi | http://dx.doi.org/10.3390/ph12020056 | |
dc.rights.ecaccessrights | openAccess | |
dc.identifier.orcid_id | 0000-0001-5005-1023 | |