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

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

ChemMedChem (2018-10-04)
Andrew W Brown, Toby Holmes, Matthew Fisher, Gillian M Tozer, Joseph P A Harrity, Chryso Kanthou
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.

MATERIALS
Product Number
Brand
Product Description

Sigma-Aldrich
Fluorescein isothiocyanate–dextran, average mol wt 70,000, (FITC:Glucose = 1:250)
Sigma-Aldrich
Monoclonal Anti-β-Tubulin antibody produced in mouse, clone TUB 2.1, ascites fluid
Sigma-Aldrich
Monoclonal Anti-Actin antibody produced in mouse, clone AC-40, ascites fluid