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J Med Chem. 1999 Feb 11;42(3):478-89.

Flavonoid-related modulators of multidrug resistance: synthesis, pharmacological activity, and structure-activity relationships.

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Laboratoire de Reconnaissance Moléculaire et Cellulaire, URA CNRS 1843, Centre d'Etudes Pharmaceutiques, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.


A series of 28 flavonoid derivatives containing a N-benzylpiperazine chain have been synthesized and tested for their ability to modulate multidrug resistance (MDR) in vitro. At 5 microM, most compounds potentiated doxorubicin cytotoxicity on resistant K562/DOX cells. They were also able to increase the intracellular accumulation of JC-1, a fluorescent molecule recently described as a probe of P-glycoprotein-mediated MDR. This suggests that these compounds act, at least in part, by inhibiting P-glycoprotein activity. As in other studies, lipophilicity was shown to influence MDR-modulating activity but was not the only determinant. Diverse di- and trimethoxy substitutions on N-benzyl were examined and found to affect the activity differently. The most active compounds had a 2,3, 4-trimethoxybenzylpiperazine chain attached to either a flavone or a flavanone moiety (13, 19, 33, and 37) and were found to be more potent than verapamil.

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