Synthesis and cytotoxic activity of certain trisubstituted azetidin-2-one derivatives as a cis-restricted combretastatin A-4 analogues.

Novel series of 1,3,4-trisubstituted azetidin-2-one derivatives 8a-p were synthesized and proposed as cytotoxic agents acting via inhibition of tubulin at the colchicine binding site. The design of the target compounds was based upon modification in the structure of the vascular targeting agent combretastatin A-4 (CA-4). The cis double bond linker in CA-4 was replaced with the azetidin-2-one ring aiming to prevent the cis/trans isomerization that suppresses the activity of CA-4, thereby enhancing its antiproliferative activity. All new compounds were investigated in vitro against MCF-7 and HCT-116 cell lines. The inhibition of tubulin polymerization by four most potent compounds 8g, 8j, 8n and 8o was also evaluated. The synthesis of the final targets was achieved adopting Staudinger reaction. Molecular modeling studies were performed to rationalize the biological results.