New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

F.A.A. van Acker*, J. Hulshof, G.R.M.M. Haenen, W.M.P.B. Menge, W.J.F. van der Vijgh, A. Bast

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Free Radic Biol Med 2001 Jul 1;31(1):31-7 Related Articles, Books, LinkOut

New synthetic flavonoids as potent protectors against doxorubicin-induced cardiotoxicity.

van Acker FA, Hulshof JW, Haenen GR, Menge WM, van der Vijgh WJ, Bast A.

Department of Medical Oncology, University Hospital Vrije Universiteit, Amsterdam, The Netherlands.

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.

Original languageEnglish
Pages (from-to)31-37
Number of pages7
JournalFree Radical Biology and Medicine
Publication statusPublished - 1 Jan 2001


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