DEVELOPMENT OF ADDUCTPPERSISTENT SPIN TRAPS/SUPEROXIDE

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Superoxide anion radical participates in a variety of pathological processes. Studies of its role and occurrence in biological systems via the spin trapping method have been impeded by the instability of the superoxide-adducts. Some recently developed phosphonated nitrones, while still far short from ideal in terms of adduct stability in vivo, have exhibited unique and intriguing improvements. This Phase I aims to carry out a series of experiments to test a proposed mechanism of stabilization for a known superoxide-adduct. Synthesis of two new, closely related nitrones will also be pursued. Contingent on a successful synthesis and to the extent the resources permit, their superoxide-adducts will be similarly examined to further validate and/or refine the proposed mechanism. Semi-empirical calculations suggest that the proposed mechanism would stabilize the superoxide-adducts by 5 to 33 Kcal/mol, and that one of the new superoxide-adducts is considerably more stable than the existing analog. An understanding of the causes of the stabilizing effects will allow a rational design of optimal spin traps for superoxide in biological systems. Such optimized spin traps may be designed, synthesized, and tested in Phase II.