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

Masami Kawase, Hiroshi Sakagami, Noboru Motohashi, Hermann Hauer, Shyam S. Chatterjee, G. Spengler, Aniko Varadi Vigyikanne, A. Molnár, J. Molnár

Research output: Contribution to journalArticle

54 Citations (Scopus)

Abstract

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
Volume19
Issue number4
Publication statusPublished - Jul 2005

Fingerprint

Coumarins
Multiple Drug Resistance
Cytotoxicity
Tumors
Modulators
Neoplasms
Cells
Gallic Acid
Verapamil
Toxicity
Fluorescence

Keywords

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

ASJC Scopus subject areas

  • Medicine(all)

Cite this

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

Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity. / Kawase, Masami; Sakagami, Hiroshi; Motohashi, Noboru; Hauer, Hermann; Chatterjee, Shyam S.; Spengler, G.; Vigyikanne, Aniko Varadi; Molnár, A.; Molnár, J.

In: In Vivo, Vol. 19, No. 4, 07.2005, p. 705-712.

Research output: Contribution to journalArticle

Kawase, M, Sakagami, H, Motohashi, N, Hauer, H, Chatterjee, SS, Spengler, G, Vigyikanne, AV, Molnár, A & Molnár, J 2005, 'Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity', In Vivo, vol. 19, no. 4, pp. 705-712.
Kawase M, Sakagami H, Motohashi N, Hauer H, Chatterjee SS, Spengler G et al. Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity. In Vivo. 2005 Jul;19(4):705-712.
Kawase, Masami ; Sakagami, Hiroshi ; Motohashi, Noboru ; Hauer, Hermann ; Chatterjee, Shyam S. ; Spengler, G. ; Vigyikanne, Aniko Varadi ; Molnár, A. ; Molnár, J. / Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity. In: In Vivo. 2005 ; Vol. 19, No. 4. pp. 705-712.
@article{3ebd3339407c49d5991b915f3221d608,
title = "Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity",
abstract = "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.",
keywords = "Coumarin, Cytotoxic activity, Multidrug resistance, Oral tumor cells, Structure-activity relationship",
author = "Masami Kawase and Hiroshi Sakagami and Noboru Motohashi and Hermann Hauer and Chatterjee, {Shyam S.} and G. Spengler and Vigyikanne, {Aniko Varadi} and A. Moln{\'a}r and J. Moln{\'a}r",
year = "2005",
month = "7",
language = "English",
volume = "19",
pages = "705--712",
journal = "In Vivo",
issn = "0258-851X",
publisher = "International Institute of Anticancer Research",
number = "4",

}

TY - JOUR

T1 - Coumarin derivatives with tumor-specific cytotoxicity and multidrug resistance reversal activity

AU - Kawase, Masami

AU - Sakagami, Hiroshi

AU - Motohashi, Noboru

AU - Hauer, Hermann

AU - Chatterjee, Shyam S.

AU - Spengler, G.

AU - Vigyikanne, Aniko Varadi

AU - Molnár, A.

AU - Molnár, J.

PY - 2005/7

Y1 - 2005/7

N2 - 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.

AB - 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.

KW - Coumarin

KW - Cytotoxic activity

KW - Multidrug resistance

KW - Oral tumor cells

KW - Structure-activity relationship

UR - http://www.scopus.com/inward/record.url?scp=21344470405&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=21344470405&partnerID=8YFLogxK

M3 - Article

C2 - 15999537

AN - SCOPUS:21344470405

VL - 19

SP - 705

EP - 712

JO - In Vivo

JF - In Vivo

SN - 0258-851X

IS - 4

ER -