Investigator: Marie Carroll, Providence College
Scientific Theme: Molecular Toxicology
Abstract: The design of new small molecules with therapeutic applications is of significant importance to modern medicine, and one approach is to mimic natural systems. The proposed research will focus on the development of 3d metal complexes that catalyze the disproportionation of superoxide, O2 -, to O2 and H2O2. High levels of O2 can lead to oxidative damage, which is associated with a number of diseases, including Parkinson’s disease, cancer, and amyotropic lateral sclerosis. Because all aerobic organisms form some amount of O2-, enzymes, superoxide dismutase (SOD) and superoxide reductase (SOR), evolved to regulate O2 levels. These enzymes all consist of redox active 3d metal ions coordinated to a variety of amino acid residues and catalyze decomposition of O2 – at high rates. Situations can arise in which O2 – levels are too high to be lowered by the natural enzymes, and therefore, therapeutic agents are necessary to process O2 and treat the resulting disease. The proposed research will focus on small molecules that mimic the structures of the active sites of SOD and SOR enzymes and could potentially be used to catalyze the disproportionation of O2 -.
In Specific Aim 1, metal complexes of ligands consisting of imine nitrogen atoms and thiolato sulfur atoms, with a range of 3d metals will be prepared, in an attempt to combine features of the various O2 regulating enzymes Because conversion of O2– to O2 and H2O2 involves a series of redox reactions, the potential reactivity of the metal complexes with O2 can be gauged by measuring their reduction potentials via cyclic voltammetry. Those metal complexes that are reduced near potentials appropriate for disproportionation of O2 will be pursued further. This approach is unique in that a range of metal centers with the same ligand set will be investigated, in order to find a complex that is optimal for reaction with O2. In Specific Aim 2, the reactivities of these complexes will be explored. Chemical redox reactions will be performed, in order to isolate species with the metals in different redox states, the formation of which must occur during the O2– disproportion reaction. Finally, the metal complexes will be reacted with O2-. Throughout the project, careful characterization of the products will be performed, in order to both verify their identities and gain insight into the types of complexes that can form. The latter will serve to better understand the mechanisms of the reactions of interest. The proposed research will serve to better inform the development of metal complexes as new therapeutic agents for treating diseases associated with the overproduction of O2-.
Human Health Relevance: This proposal seeks to synthesize metal complexes that mimic the active sites and functionality of O2 regulating enzymes. Because high levels of O2- are associated with a variety of diseases, metal complexes that convert O2- to O2 and H2O2 could potentially be used as therapeutics for the treatment of diseases related to oxidative damage.