Synthesis, evaluation and structural studies of antiproliferative tubulin-targeting azetidin-2-ones
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2011Citation:
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, 2306-2325Download Item:
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.
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Health Research Board (HRB)
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http://people.tcd.ie/mmeeganhttp://people.tcd.ie/nioboyle
http://people.tcd.ie/dzistrer
http://people.tcd.ie/tmccabe
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Bioorganic & Medicinal Chemistry19
7
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Pharmacology, azetidinone ring scaffoldSubject (TCD):
CancerMetadata
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