Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity

Masami Kawase, Hiroshi Sakagami, Noboru Motohashi, Hermann Hauer, Shyam S. Chatterjee, Gabriella Spengler, Aniko Varadi Vigyikanne, Annamaria Molnár, Joseph Molnár

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54 Citations (Scopus)


A preliminary exploration of coumarin derivatives as novel multidrug resistance (MDR) modulators was carried out to determine the basic features of the structure responsible for the MDR reversal activity. Among 44 coumarins, 14 compounds moderately induced the reversal of MDR (fluorescence activity ratio (FAR) values > 1). The most active compound, 6-hydroxy-3-(2-hydroxyethyl)-4-methyl-7-methoxycoumarin [C34], was equally potent as a MDR modulator verapamil. These data show a relationship between the chemical structure and MDR-reversal effect on tumor cells. All coumarins tested were more cytotoxic against tumor cells than normal cells. Several compounds displayed potent cytotoxic activities (CC50 15-29 μg/mL in HSC cells), comparable with that of gallic acid (CC50=24 μg/mL). Both 6-hydroxy-7-methoxy-4-methyl-3-isopropylcoumarin [C43] and 3-ethyl-6-hydroxy-7-methoxy-4-methylcoumarin [C44] showed the highest tumor-specific cytotoxicity (SI value=4.1 and 3.6, respectively). We conclude that coumarins are potentially potent new MDR modulators with low toxicity against normal cells. A deeper understanding of the relationship between their structures and their potency will contribute to the design of optimal agents.

Original languageEnglish
Pages (from-to)705-712
Number of pages8
JournalIn Vivo
Issue number4
Publication statusPublished - Jul 1 2005


  • Coumarin
  • Cytotoxic activity
  • Multidrug resistance
  • Oral tumor cells
  • Structure-activity relationship

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Pharmacology

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  • Cite this

    Kawase, M., Sakagami, H., Motohashi, N., Hauer, H., Chatterjee, S. S., Spengler, G., Vigyikanne, A. V., Molnár, A., & Molnár, J. (2005). Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity. In Vivo, 19(4), 705-712.