New Biologically Relevant Sulfur Radical Cation Chemistry

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The Organic and Macromolecular Chemistry Program supports Professor Richard S. Glass at the University of Arizona who proposes to examine the chemical basis for the hypothesis that the pathogenesis of Alzheimer's disease involves oxidation. It is proposed that Met-35 of beta-amyloid peptides was responsible for initiating this oxidation by reducing metal ions, i.e. Fe(III) or Cu(II), which then participate in Fenton-type reactions to generate the potent oxidant OH radical. The proximity of an amide or phenyl ring to the Met sulfur was invoked to lower the oxidation potential of the sulfur by promoting electron-transfer generating a sulfur radical cation.Professor Glass will examine neighboring group participation by amide and aromatic rings on electron transfer from thioethers specifically assessing the nature of bonding in these unique systems. To accomplish these goals a combination of methods will be used: (1) design and synthesis of conformationally constrained molecules, (2) electrochemical studies, (3) pulse radiolysis studies, (4) electron paramagnetic resonance (EPR) spectroscopic studies, (5) photoelectron spectroscopy (PES) studies and (6) computational studies (theoretical calculations). The use of such diverse methodologies will require the collaboration of several laboratories. In addition to uncovering novel chemistry, the proposed studies should provide insight and tools for evaluating the basis for Alzheimer's disease.The Organic and Macromolecular Chemistry Program supports Professor Richard S. Glass whose proposed studies will involve undergraduate, graduate and postdoctoral students as well as collaborations with the University of Kansas, Notre Dame University and Arizona State University. Indeed a unique multi-institutional consortium will be empowered to address fundamental chemical questions with a wide array of potent methods and expertise. The proposed work may lead to an understanding of the chemical basis of Alzheimer's disease. Such an understanding may result in improved diagnosis or treatment for this devastating disease, which is a major health problem currently in the U.S. and increasing with the aging population.