Therapeutic Chelators for the Twenty First Century: New Treatments for Iron and Copper Mediated Inflammatory and Neurological Disorders

Superoxide, hydrogen peroxide, hydroxyl radicals and peroxynitrite are collectively termed reactive oxygen and nitrogen species (RONS). They have been ascribed an important role in oxidative stress contributing to the progression of inflammatory diseases. RONS generating systems include the inflammatory response, enzymatic pathways and as side products of catabolism. Protective enzymes exist for the regulation of RONS such as superoxide dismutase, catalase and glutathione peroxidase. Furthermore, vitamins play a secondary role in deactivating RONS. The redox active metal ions such as ferrous and cuprous ions are released from the storage proteins ferritin and caeruloplasmin by RONS. Redox active metal ions further activate/generate RONS and thus perpetuate their damaging effects. Here we report recent therapies that focus on intervening in the roles of metal ions in oxidative stress. These include: i) chelators which complex labile metal ions to form antioxidant enzyme mimetics, ii) site-specific RONS scavengers, where dual functionality colocalizes the scavenger and chelation centre to direct scavenging, and iii) redox silencing, metal complexation with concomitant stabilization of the metal ion in the oxidized form to prevent further activation of RONS. The rationale for this new therapeutic approach and recent advances will be presented in this review.