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The Metabolic Fate of iso Combretastatin A‐4 in Human Liver Microsomes: Identification, Synthesis and Biological Evaluation of Metabolites
Author(s) -
Soussi Mohamed Ali,
Aprile Silvio,
Messaoudi Samir,
Provot Olivier,
Del Grosso Erika,
Big Jérôme,
Dubois Joëlle,
Brion JeanDaniel,
Grosa Giorgio,
Alami Mouad
Publication year - 2011
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.201100193
Subject(s) - combretastatin , hydroxylation , metabolite , antimitotic agent , demethylation , chemistry , human liver , microsome , biochemistry , stereochemistry , tubulin , computational biology , biology , in vitro , microtubule , enzyme , gene , gene expression , genetics , dna methylation
Digesting drugs! Due to the structural differences between iso combretastatin A‐4 ( iso CA‐4) bearing a 1,1‐diarylethylene scaffold and the natural Z ‐stilbene combretastatin A‐4 (CA‐4), we examined the metabolic profile of iso CA‐4 using human liver fractions. Seven iso CA‐4 metabolites, resulting from O‐demethylation, hydroxylation of the aromatic rings were identified and synthesized. Evaluation of their cytotoxicity and their ability to inhibit tubulin polymerization (ITP activity) led us to identify a metabolite with a strong antimitotic activity comparable to that of iso CA‐4.