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

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