Problems 1 to 4 bear upon peroxidase, catalase and cytochrome P-450 chemistries which relate directly to problems in toxicology and oncology. 1. Synthesized water soluble (non mu-oxo dimer forming) metal (III) porphyrins will be used in determining the mechanism of the formation of metallo-oxo porphyrins will be used in determining the mechanism of the formation of metallo-oxo porphyrins at the compound I level of oxidation. RCO3H and ROOH species will be used as oxygen transfer agents and the mechanism of the rate limiting step (12-vs.2e-) and the mechanism of the overall reaction (homolytic vs. heterolytic 0-0 bond cleavage) will be determined. Influence of general and specific catalysis, and added ligands upon the rate constants for oxygen transfer will be studied. 2. A major effort will be mounted to synthesize iron (III) porphyrins possessing a """"""""straped on"""""""" thiolate ligand to assess the role of the cysteine thiolate ligand of the cytochrome P-450 enzymes in determining the structure and reactivity of the putative compound I species. 3. Both chemical and electrochemical kinetic techniques are to be used in the determination of the second order rate constant for reaction of compound I species with organic substrates. 4. Recently discovered complex redox reactions of manganese(III) porphyrins in the presence of strongly basic oxyanions will be investigated in detail. Studies 5 to 7 deal with flavins and pteridines. 5. A search for the mechanistic reasons as to why dihydroflavins reduce H2O2 very slowly while the reaction with tetrahydropterins occurs in miliseconds. 6. Explore the reaction of thiol esters with flavins to determine the role of covalent intermediates in the formation of alpha,beta-unsaturation. 7. Search for pathways in the reaction of dihydroflavins with O2 which provide covalent adducts other than the 4a-hydroperoxide. Problems 8 to 10 are in the area of Methoxatin chemistry, 8. The positions of cu (II) ligation will be determined. 9. Analogs will be synthesized to determine the infuence of change in electrochemical potential on cofactor activity with a reconstitutable apoenzyme. 10. Influence of structure of PQQ compounds on the mechanism of amine oxidation will be studied. A problem cental to the mechanism of flavin, porphyrin, dihydropyrine and metallo porphyrin reactions is the putative role of radical intermediates. 11. The super-radical trap substituent 2t,3t-diphenyl-cyclopropyl will be incorporated into suitable molecules to assess the intermediacy of radical intermediates in model and enzymatic reactions. Studies (12) of the role of carbinolamine vs. imines intermediates in enolization reactions will be continued.
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