Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity.
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 microg/mL in HSC cells), comparable with that of gallic acid (CC50 = 24 microg/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.
Faculty of Pharmaceutical Sciences, Josai University, Saitama, Japan. kawasema@josai.ac.jp
Masami
M
Kawase
Hiroshi
H
Sakagami
Noboru
N
Motohashi
Hermann
H
Hauer
Shyam S
SS
Chatterjee
Gabriella
G
Spengler
Aniko Varadi
AV
Vigyikanne
Annamaria
A
Molnár
Joseph
J
Molnár
D045744:Cell Line, Tumor / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003374:Coumarins / Q000737:chemistry / Q000145:classification / Q000494:pharmacology*; D018432:Drug Resistance, Multiple; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004354:Drug Screening Assays, Antitumor; D005347:Fibroblasts / Q000187:drug effects* / Q000473:pathology; D006801:Humans; D015394:Molecular Structure; D009369:Neoplasms / Q000188:drug therapy*; D021281:Quantitative Structure-Activity Relationship; D014700:Verapamil / Q000494:pharmacology
D003374:Coumarins; D014700:Verapamil