Document Type



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Organic Chemistry, Biochemistry and molecular biology

Publication Details

Journal of Medicinal Chemistry, December 2010, Vol. 53, No. 24, Pages 8569 – 8584


The synthesis and antiproliferative activity of a new 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. These novel compounds are also substituted at position 3 of the β-lactam ring with an aryl ring. A number of analogues showed potent nanomolar activity in human MCF-7 and MDA-MB-231 breast cancer cell lines, displayed in vitro inhibition of tubulin polymerization and did not cause significant cytotoxicity in normal murine breast epithelial cells. 4-(4-Methoxyaryl)-substituted compound 32, 4-(3-hydroxy-4-methoxyaryl)-substituted compounds 35 and 41 and the 3-(4-aminoaryl)-substituted compounds 46 and 47 displayed the most potent anti-proliferative activity of the series. β-Lactam 41 in particular showed sub-nanomolar activity in MCF-7 breast cancer cells (IC50 = 0.8 nM) together with significant in vitro inhibition of tubulin polymerization and has been selected for further biochemical assessment. These novel β-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin.