Chapter 12. Nitroxide Intervention in Oxidative and Free Radical Damage in Biology and Disease

Nitroxides are a diverse range of stable free radicals with applications in industrial polarisation processes and imaging contrasting, and over the last 30 years mounting evidence has demonstrated their therapeutic potential in mitigating diseases where oxidative damage is implicated. This is due to their radical oxidative/antioxidant duality and ability to readily cross cell membranes. In biological tissues, nitroxides are balanced between radical and antioxidant states depending on reducing or hypoxic conditions. For example, in cancer biology where conditions are typically hypoxic, the nitroxide radical induces further oxidative stress in metabolically stressed cancer cells and induces cell death, whereas nitroxides are reduced to a non-radical hydroxylamine antioxidant form in healthy cells, thereby conferring cytoprotection from radiotherapy. Nitroxides-derived antioxidant activities have also been described in terms of superoxide dismutase mimetics and inhibitors of hypochlorous acid production from neutrophil-derived myeloperoxidase during inflammatory insults. As such, nitroxides have potential applications in chronic inflammatory disorders by abrogating the production of more powerful oxidants which mediate tissue injury and cell death. Although nitroxides typically have a short half-life, recent developments to sterically stabilised nitroxides have seen biological improvements in their half-life and subsequent efficacies. Further structural variations with altered side-chain properties offer subcellular delivery to improve the bio-activity of nitroxides, thereby offering major new opportunities to exploit both the radical and antioxidant redox activity of nitroxides for therapeutic advantage in a wide range of human disorders.