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 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.
Ferté
J
J
Laboratoire de Reconnaissance Moléculaire et Cellulaire, URA CNRS 1843, Centre d'Etudes Pharmaceutiques, 5, rue J.B. Clément, 92296 Châtenay-Malabry Cedex, France.
Kühnel
J M
JM
Chapuis
G
G
Rolland
Y
Y
Lewin
G
G
Schwaller
M A
MA
D000903:Antibiotics, Antineoplastic / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D004317:Doxorubicin / Q000494:pharmacology; D018432:Drug Resistance, Multiple; D005419:Flavonoids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D020014:K562 Cells; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D013329:Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology