Oxidative stress is implicated in a wide variety of diseases, including diabetes, inflammation, post- ischemia reperfusion, UV exposure, atherosclerosis, aging, macular degeneration, and neurodegeneration. Lipid peroxidation, DNA hydroxylation, and protein modification are markers of oxidative stress that result primarily from reactions with the highly reactive hydroxyl radical, OH, itself a product of iron-catalyzed reactions with oxygen species. Whereas iron is an essential and beneficial component of healthy cells, this deleterious reactivity suggests that labile iron in the cell provokes serious damage. Our long-term goals are to develop medicinal iron chelating agents that selectively inhibit this deleterious iron-promoted damage at the site of oxidative stress while avoiding toxicity commonly associated with iron chelation therapy. In addition to being potentially useful medicinal agents, the proposed pro-chelators will also serve as fluorescent probes to visualize the role of iron in oxidative stress in living cells. In order to achieve these goals, this proposal focuses on the chemistry required to synthesize (Specific Aim 1) and characterize (Specific Aim 2) new families of pro-chelators in which a masking group blocks key metal-binding functionalities of otherwise high-affinity iron chelators. The masking groups are boronate esters, since these groups are deprotected by hydrogen peroxide, a component of oxidative stress.
In Specific Aim 3 we develop fluorescent analogs to probe iron-promoted oxidative stress inside living cells. Once the synthesis and characterization establishes their in vitro properties, this new class of molecules will be tested in cell culture to validate their efficacy for protecting cells against oxidative damage by removing iron at the source of oxidative stress (Specific Aim 4). Currently available chelation therapies face toxic side reactions that alter healthy metal distribution and inhibit critical metalloenzymes. In the absence of hydrogen peroxide, the proposed masked chelators will be innocuous bystanders that will not interfere with beneficial metals. Disease conditions that increase hydrogen peroxide levels, however, activate and unmask a potent chelator that sequesters and removes the iron that is the source of OH generation. Unlike typical antioxidants that neutralize harmful free radicals only after they are produced, effective iron chelators can eliminate their production altogether by disabling the source. The molecules proposed herein represent a promising new strategy with potential impact on a number of human diseases, especially those where normal metal ion homeostasis is impaired or where aberrant metal accumulation takes place. Degenerative diseases like Parkinson's disease and age-related macular degeneration are just two examples.
Over a million Americans suffer from Parkinson's disease, a progressive form of neurodegeneration with no known cure that is estimated to cost $25 billion per year in direct and indirect costs in the United States. Although its cause is not known, emerging hypotheses implicate iron-induced oxidative stress as a source of neuronal damage. The new pro-chelator molecules proposed herein are designed to protect cells against precisely this type of damage, and therefore represent a promising new strategy with the potential to impact not only Parkinson's disease, but also other neurodegenerative conditions, age-related macular degeneration, and a wide variety of other human diseases associated with oxidative stress.
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