Carr, M.Greene, L.M.Knox, A.J.S.Lloyd, D.G.Zisterer, D.M.Meegan, M.J.2025-12-172025-12-172010European Journal of Medicinal Chemistry, 2010; 45(12):5752-57660223-52341768-3254https://hdl.handle.net/1959.8/151898The synthesis and study of the structureeactivity 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.enCopyright 2010 Elsevier Masson2-azetidinoncombrestatin A-4 analoguescytotoxicitystructure-activitytubulinβ-lactamJournal article10.1016/j.ejmech.2010.09.033000285485000026