| A striking characteristic of neurodegenerative diseases such as Parkinson's and Alzheimer's diseases is a localized increase in oxidative stress in the disease-affected region of the brain. The same regions that experience oxidative insult exhibit augmented iron loads, suggesting a central role of metal-catalyzed oxidative stress in pathogenesis. The hydroxyl radical, OH· , is a highly toxic radical that ensues from the interaction of redox-active metals, such as copper and iron, with hydrogen peroxide in biological systems. The oxidative stress induced by OH· is thought to be involved in the aging process and has been implicated in both neurodegeneration and macular degeneration.;Described here is the development of prochelators that have little affinity for metal ions until a protective mask is selectively removed by hydrogen peroxide to reveal a high affinity ligand that scavenges the redox-active metal. Whereas traditional iron chelators bind iron non-selectively, boronic ester prochelators bind iron only after exposure to hydrogen peroxide. The prochelator is designed to sequester potentially dangerous iron without competing with metal-essential proteins and altering healthy metal ion homeostasis. Spectroscopic characterization of several boronic ester prochelators reveals that the rate of unmasking by hydrogen peroxide, as well as the lipophilicity and strength of iron binding, can be tuned by modifications to the parent structure. The ability of the prochelators to inhibit hydroxyl radical formation in vitro was demonstrated by the deoxyribose assay. The protective effect of the prochelators against H2O2-induced cell death is demonstrated in a macular degeneration cell culture model.;The selective degeneration of dopaminergic neurons containing neuromelanin and concurrent elevation of iron concentrations in these neurons is a hallmark of Parkinson's disease. The final chapter discusses the characterization of Fe(III)-coordination properties of neuromelanin building blocks in aqueous solution by anaerobic pH-dependent spectrophotometric titrations. In aqueous solution at physiological pH, neuromelanin components leave open coordination sites on the iron center. Furthermore, oxidation studies reveal that iron accelerates the air oxidation of neuromelanin components. |
