Evaluation of Sydnone-Based Analogs of Combretastatin A-4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy

The combretastatins have attracted significant interest as small molecule therapies for cancer due to their ability to function as vascular disrupting agents. We have successfully prepared a range of combretastatin analogs that are based on a novel sydnone heterocycle core, and their potential as tubulin has been assessed in vitro and in vivo. The most potent candidate was found to disrupt microtubules and affect cellular morphology at sub-micromolar levels. Moreover, it was found to bind reversibly to tubulin and significantly increase endothelial cell monolayer permeability, in a similar manner to combretastatin A4. Surprisingly, the compound did not exhibit efficacy in vivo, possibly due to rapid metabolism.