Evaluation of Sydnone‐Based Analogues of Combretastatin A‐4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy. (8th November 2018) - Brown, Andrew W.
Abstract: 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 analogues that are based on a novel sydnone heterocycle core, and their potential as tubulin binders 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. Abstract : Cis is the answer ! A family of novel configurationally fixed combretastatin analogues has been prepared that is based on a sydnone heterocycle core. The most potent analogue was found to display tubular binding and disruption, and to affect cellular morphology and permeability in a similar manner to combretastatin A4.