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

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 (beta-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 G(2)/M arrest of the cell cycle in human MDA-MB-231 breast cancer cells, with similar activity to that of CA-4. These novel beta-lactam compounds are identified as potentially useful scaffolds for the further development of antitumour agents which target tubulin. (C) 2010 Elsevier Masson SAS. All rights reserved.