New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity

被引:44
作者
Van Acker, FAA
Hulshof, JW
Haenen, GRMM
Menge, WMPB
van der Vijgh, WJF
Bast, A
机构
[1] Free Univ Amsterdam Hosp, Dept Med Oncol, NL-1081 HV Amsterdam, Netherlands
[2] Univ Maastricht, Dept Pharmacol & Toxicol, Maastricht, Netherlands
[3] Vrije Univ Amsterdam, Fac Chem, Dept Pharmacochem, LACDR, Amsterdam, Netherlands
关键词
flavonoids; doxorubicin; cardiotoxicity; free radicals; lipid peroxidation; hepatocytes; left atrium;
D O I
10.1016/S0891-5849(01)00546-9
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
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 Fe2+/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC50 values ranged from 0.2 to 37 muM. 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 muM) 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 gd (N-(3-(3',4'-dihydroxyflavon-7-yl)oxypropyl)-N,N,N-trimethylammonium cloride) and 10e (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. (C) 2001 Elsevier Science Inc.
引用
收藏
页码:31 / 37
页数:7
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