Evidence for peroxidative oxidation of substituted piperidine nitroxides, acting as apoptosis inducers in Yoshida sarcoma cells in vivo

The results presented herein clearly indicate that nitroxide derivatives - free radicals are effective as substrates for one-electron oxidation in the peroxidase cycle involving hydrogen peroxide, which have been the subject of considerable controversy. This oxidation is catalyzed enzymatically and it might occur in tumor cells (in vivo) where the level of ROS (H2O2 and O- 2(-.)) is increased. The result of this reaction involving hydrogen peroxid e is the obligative formation of the oxo-ammonium cation involved in the su peroxide dismutase-mimic reaction of nitroxides with superoxide and/or in r eaction with H2O2 leading to superoxide formation and regeneration of the p arent nitroxide molecule. The efficiency of this enzymatically catalyzed ox idation of nitroxide(s) depends on the structure of the substituent in posi tion 4 of nitroxide ring as follows: - OCH3>-NHCOCH3>-NHCOCH(2)CH3. Notably , the reduced nitroxide salt was not substrate for peroxidatic oxidation cl early indicating the importance of the free radical moiety of the nitroxide molecule. These findings may have some relevance in the recent investigati ons of antioxidant properties/mechanisms of nitroxides. Based on these cons iderations we hypothesize that the administration of oxidizable free radica l nitroxide compounds antioxidants may be a useful strategy in the treatmen t and investigations of cancer diseases. An in vivo study ("Screening rest of chemicals employing Yoshida Sarcoma animals") was carried out to verify whether the structure and/or the chain length of substituent of oxidizable nitroxide derivatives - antioxidants could influence their apoptotic activi ty. The results repelled in this study are encouraging as we found a limite d correlation between the molecular oxidative properties of nitroxides unde r study, their structure and antitumor (apoptotic) action. In conclusion, t his work demonstrates that investigation of the structure - dependent oxida tion of antioxidatively acting nitroxides can become a very important step in their future screening and selection for applications in vivo and in vit ro.