Kinetics and Mechanisms: Oxidation of Some Selected sulfur Compounds of Physiological and Environmental Importance

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This award in the Inorganic, Bioinorganic and Organometallic Chemistry program supports research by Professor Reuben Simoyi at Portland State University to elucidate the kinetics and mechanisms of the oxidation of some selected organosulfur compounds of physiological and environmental importance. The mechanistic data will be used in rationalizing the organosulfur compounds' observed physiological effects and to predict toxicities. This proposal will thus concentrate on thioamides, thiocarbamides, thiocarbamates, dithiocarbamates and aminothiols. The general physiological oxidants that will be used are molecular oxygen, hydrogen peroxide, peracids, HOCl, HOBr, and superoxide, hydroxyl and peroxynitrite radicals. Due to the recent wide-spread use of chlorine dioxide as an oxidant and water disinfectant, it will also be used as an oxidant of selected agricultural organosulfur compounds. The organosulfur compounds are expected to form S-oxides, dioxides and trioxides before forming sulfate and a urea analogue of the thio-compound. The major theme of this proposal will be to synthesize and characterize (X-ray structure, reactivity, chemical properties) these postulated sulfur oxo-acids. Their biological activities will also be evaluated for the possibility of deriving reactive oxygen species in aerobic environments as well as probing for possible toxicity effects as quantified by DNA damage experiments. Work reflecting the importance of S-nitrosothiols, RSNO's, in the physiological environment will study the relevant chemistry of formation of nitrosothiols (kinetics and mechanism of formation and decomposition). A mechanistic understanding of thiol nitrosation should enable the design of RSNO's with better pharmacokinetics properties. This research straddles the areas of physical chemistry and biophysical chemistry by deriving mechanistic and kinetic data that can be utilized to rationalize the observed physiological effects of specific biologically-active organosulfur compounds. A large component of this grant involves the training of undergraduate and graduate students to perform this cross-disciplinary research. The PI's laboratory is presently training a number students at the doctoral level from disadvantaged backgrounds, and a major portion of this requested funding will be used to educate under-represented minorities.