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Evaluation of Sydnone‐Based Analogues of Combretastatin A‐4 Phosphate (CA4P) as Vascular Disrupting Agents for Use in Cancer Therapy
Author(s) -
Brown Andrew W.,
Holmes Toby,
Fisher Matthew,
Tozer Gillian M.,
Harrity Joseph P. A.,
Kanthou Chryso
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201800567
Subject(s) - combretastatin , sydnone , in vivo , chemistry , tubulin , in vitro , pharmacology , microtubule , biophysics , biochemistry , biology , microbiology and biotechnology , ring (chemistry) , organic chemistry
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.