Lead identification of conformationally restricted β-lactam type combretastatin analogues : synthesis, antiproliferative activity and tubulin targeting effects
Date
2010
Authors
Carr, M.
Greene, L.M.
Knox, A.J.S.
Lloyd, D.G.
Zisterer, D.M.
Meegan, M.J.
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Journal article
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European Journal of Medicinal Chemistry, 2010; 45(12):5752-5766
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Abstract
The 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.
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Copyright 2010 Elsevier Masson