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

J Med Chem. 1999 Feb 11;42(3):478-89. doi: 10.1021/jm981064b.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antibiotics, Antineoplastic / pharmacology
  • Calcium Channel Blockers / pharmacology
  • Doxorubicin / pharmacology
  • Drug Resistance, Multiple*
  • Flavonoids / chemical synthesis*
  • Flavonoids / chemistry
  • Flavonoids / pharmacology
  • Humans
  • K562 Cells
  • Magnetic Resonance Spectroscopy
  • Mass Spectrometry
  • Structure-Activity Relationship
  • Verapamil / pharmacology


  • Antibiotics, Antineoplastic
  • Calcium Channel Blockers
  • Flavonoids
  • Doxorubicin
  • Verapamil