New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.
A series of 3,7-disubstituted-2(3',4'-dihydroxyphenyl) flavones has been studied as potential cardioprotective agents in doxorubicin antitumor therapy. The influence of substituents on the 3 and 7 position of the flavone nucleus on antioxidant activity cytotoxicity and cardioprotective properties was explored to improve the activity of our lead compound 7-monohydroxyethylrutoside. In the protection against Fe(2+)/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC(50) values ranged from 0.2 to 37 microM. In general, the 3-substituted flavones were the most potent compounds in this assay. The cytotoxicity of the new compounds was tested (up to 250 microM) in hepatocytes. LDH leakage ranged from 2.6-29.2%, whereas the GSH concentrations decreased to 87.3-41.3%. Only four compounds out of this series protected the isolated mouse left atrium against doxorubicin-induced toxicity. Because of the positive inotropic effect of 8d (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium chloride) and 10c (3-hydroxyethoxy-7,3',4'-trihydroxyflavone) on the atrium, compounds 9i (3',4'-dihydroxy-3-glucosylflavone) and 10d (N-(3-(7,3',4'-trihydroxyflavon-3-yl)oxypropyl)-N,N,N-trimethylammonium chloride) were selected to be evaluated as cardioprotective agents in vivo.
van Acker
F A
FA
Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands. f.vanacker@azvu.nl
Hulshof
J W
JW
Haenen
G R
GR
Menge
W M
WM
van der Vijgh
W J
WJ
Bast
A
A
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000009:adverse effects*; D000975:Antioxidants / Q000494:pharmacology; D004195:Disease Models, Animal; D004317:Doxorubicin / Q000009:adverse effects*; D004359:Drug Therapy, Combination; D005419:Flavonoids / Q000494:pharmacology* / Q000627:therapeutic use; D005978:Glutathione / Q000378:metabolism; D006325:Heart Atria / Q000187:drug effects / Q000378:metabolism; D006331:Heart Diseases / Q000139:chemically induced / Q000378:metabolism / Q000517:prevention & control*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D015227:Lipid Peroxidation; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008862:Microsomes, Liver / Q000187:drug effects / Q000378:metabolism; D015394:Molecular Structure; D020011:Protective Agents / Q000494:pharmacology* / Q000627:therapeutic use; D051381:Rats; D017208:Rats, Wistar
D000903:Antibiotics, Antineoplastic; D000975:Antioxidants; D005419:Flavonoids; D020011:Protective Agents; D004317:Doxorubicin; D007770:L-Lactate Dehydrogenase; D005978:Glutathione