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 Fe2+/vitamin C-induced microsomal lipid peroxidation (LPO assay), IC50 values ranged from 0.2 to 37 μM. 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 μM) 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 cloride) 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.