dc.contributor.author | MEEGAN, MARY | en |
dc.contributor.author | GREENE, LISA | en |
dc.contributor.author | O'BOYLE, NIAMH | en |
dc.contributor.author | MCCABE, THOMAS | en |
dc.contributor.author | ZISTERER, DANIELA | en |
dc.contributor.author | LLOYD, DAVID | en |
dc.date.accessioned | 2011-04-19T13:44:21Z | |
dc.date.available | 2011-04-19T13:44:21Z | |
dc.date.issued | 2011 | en |
dc.date.submitted | 2011 | en |
dc.identifier.citation | O'Boyle, NM, Greene, LM, Bergin, O, Fichet, JB, McCabe, T, Lloyd, DG, Zisterer, DM, Meegan, MJ, Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones, Bioorganic & Medicinal Chemistry, 19, 7, 2011, 2306-2325 | en |
dc.identifier.other | Y | en |
dc.identifier.uri | http://hdl.handle.net/2262/54923 | |
dc.description | PUBLISHED | en |
dc.description.abstract | A series of azetidin-2-ones substituted at positions 2, 3 and 4 of the azetidinone ring scaffold were synthesised and evaluated for antiproliferative, cytotoxic and tubulin binding activity. In these compounds, the cis double bond of the vascular targeting agent combretastatin A-4 is replaced with the azetidinone ring in order to enhance the antiproliferative effects displayed by combretastatin A-4 and prevent the cis/trans isomerization that is associated with inactivation of combretastatin A-4. The series of azetidinones was synthetically accessible via the Staudinger and Reformatsky reactions. Of a diverse range of heterocyclic derivatives, 3-(2-thienyl) analogue 28 and 3-(3-thienyl) analogue 29 displayed the highest potency in human MCF-7 breast cancer cells with IC50 values of 7 nM and 10 nM respectively, comparable to combretastatin A-4. Compounds from this series also exhibited potent activity in MDA-MB-231 breast cancer cells and in the NCI60 cell line panel. No significant toxicity was observed in normal murine breast epithelial cells. The presence of larger, bulkier groups at the 3-position, for example 3-naphthyl derivative 21 and 3-benzothienyl derivative 26, resulted in relatively lower antiproliferative activity in the micromolar range. Tubulin-binding studies of 28 (IC50=1.37 ?M) confirmed that the molecular target of this series of compounds is tubulin. These novel 3-(thienyl) ?-lactam antiproliferative agents are useful scaffolds for the development of tubulin-targeting drugs. | en |
dc.format.extent | 2306-2325 | en |
dc.language.iso | en | en |
dc.relation.ispartofseries | Bioorganic & Medicinal Chemistry | en |
dc.relation.ispartofseries | 19 | en |
dc.relation.ispartofseries | 7 | en |
dc.rights | Y | en |
dc.subject | Pharmacology | en |
dc.subject | azetidinone ring scaffold | en |
dc.title | Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones | 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/mmeegan | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/nioboyle | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/dzistrer | en |
dc.identifier.peoplefinderurl | http://people.tcd.ie/tmccabe | en |
dc.identifier.rssinternalid | 71208 | en |
dc.subject.TCDTheme | Cancer | en |
dc.identifier.rssuri | http://dx.doi.org/10.1016/j.bmc.2011.02.022 | en |
dc.contributor.sponsor | Health Research Board (HRB) | en |