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Cytotoxic activities and metabolic studies of new combretastatin analogues

par Macé, Yohan;Bony, Emilie;Delvaux, David;Pinto, Adan;Mathieu, Véronique ;Kiss, Robert ;Feron, Olivier;Quetin-Leclercq, Joëlle;Riant, Olivier
Référence Medicinal chemistry research, 24, 8, page (3143-3156)
Publication Publié, 2015-04

Article révisé par les pairs

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Résumé :

A new series of combretastatin analogues with B-ring modifications were synthesized and evaluated for their cytotoxicity against one endothelial (HUVEC) and three tumor cell lines, e.g., the LoVo colon, the PC-3 prostate, and the U373 glioma cancer models. These new combretastatin analogues showed differential cytotoxic activities, cis derivatives 13 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole N 1-oxide and 14 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2,5]thiadiazole exhibiting interesting cytotoxicity both on endothelial and on tumor cells. Unlike the cis benzofurazan 12 5-(2-Z-trimethoxyphenylethenyl)benzo[1,2-c]1,2,5-oxadiazole, induction of apoptosis by 13 appeared to be through caspase-3 activation. Metabolic investigations showed a positive correlation between highly metabolized compounds and cytotoxic activity, suggesting that highly cytotoxic derivatives may act as pro-drug via a reductive metabolization to more active metabolites.