Redox Properties and Cytotoxicity of Synthetic Isomeric Mitochondriotropic Derivatives of the Natural Polyphenol Quercetin

Mitochondria-targeted redox-active polyphenol derivatives are being developed to affect redox processes in the organelles and as tools either to protect cells from oxidative damage or to precipitate their death. The properties of such compounds may be altered by substituents introduced to enhance mitochondrial delivery. Accordingly, we have characterized the redox behaviour of two isomeric mitochondriotropic quercetin-based compounds, 3O- and 7O-[4-triphenylphosphonio)butyl]quercetin iodide. In both cyclic voltammetric determinations of the oxidation potential and in 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical scavenging assays, the 7-substituted isomer behaved much like quercetin itself, whereas the 3-substituted isomer was less reactive. Low mu M concentrations of either compound increased superoxide radical anion formation in cultured cells; both compounds were also cytotoxic. The 7-substituted derivative proved to be more active in both types of assays, thus emerging as the isomer of choice for further bioactivity studies and in efforts to understand the link between redox properties, pro-oxidant behaviour and cytotoxicity.