Vascular disrupting agents (VDAs), as Combretastatin A4 (CA-4), are potential anticancer agents. CA-4 targets the colchicine binding site of the � subunit of endothelial cell tubulin. The depolymerization of microtubules and disorganization of actin and tubulin that caused by CA-4 selectively damage the tumor vasculature and close the blood supply to solid tumors, causing massive tumor cell necrosis. Herein, we designed a group of novel conformationally restricted analogs of Combretastatin A4 to act as vascular disrupting agents (VDAs) with improved physical and biological characteristics. The newly synthesized compounds exhibited enhanced solubility in aqueous biological media, improved stability and longer shelf life than Combretastatin A4. The new compounds were evaluated for their cytotoxic activity as well as their tubulin polymerization inhibitory activity. Finally, the docking studies suggested an improved binding affinity of some of the new analogues to heterodimer tubulin.

Synthesis and cytotoxic activity of novel conformationally restricted analogs of Combretastatin A4

247th National Meeting (2014)

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