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Eur J Med Chem. 2010 Dec;45(12):5752-66. doi: 10.1016/j.ejmech.2010.09.033. Epub 2010 Sep 22.

Lead identification of conformationally restricted β-lactam type combretastatin analogues: synthesis, antiproliferative activity and tubulin targeting effects.

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School of Pharmacy and Pharmaceutical Sciences, Centre for Synthesis and Chemical Biology, Trinity College Dublin, Dublin 2, Ireland.


The synthesis and study of the structure-activity relationships of a series of rigid analogues of combretastatin A-4 are described which contain the 1,4-diaryl-2-azetidinone (β-lactam) ring system in place of the usual ethylene bridge present in the natural combretastatin stilbene products. The 1,4-diaryl-2-azetidinones are unsubstituted at C-3, or contain methyl substituent(s) at C-3. The most potent compounds 12d and 12e display antiproliferative activity at nanomolar concentrations when evaluated against the MCF-7 and MDA-MB-231 human breast carcinoma cell lines. 12d exerts antimitotic effects through an inhibition of tubulin polymerisation and subsequent G2/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.

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