The goal of the proposed research is to further develop aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of O2 and nitrogen oxides (NOx). Research subprojects include: (1) Detailed studies of primary copper(I)-O2 adducts,. For several Cu(II)(O2?-) species we will examine their protonation-reduction chemistry to give Cu(II)-(hydro)peroxides. Acids and reducing agents will be varied and kinetics studied, to provide insights concerning electron-transfer, maybe involving proton-coupled electron-transfer (PCET). Cu(II)(O2?-) complex reactivity with C-H or O-H substrates will be also studied mechanistically to establish their oxidizing capabilities. Cu(II)(O2?-) species with one thioether ligand donor will also be include; we will explore the possibility that O2- chemistry involves methionine sulfur radical cation formation, a possible new paradigm in the field. (2) A specific set of Cu(II)2-OOR complexes with varied R (= H, alkyl or acyl) will be subjected to acids of varying pKa values and investigated for their O-O reductive cleavage chemistry. Kinetic studies, isotope effect determination and product analyses will be carried out in order to elucidate the mechanism of O- O cleavage, homolytic or heterolytic. We hope to identify high-valent copper-oxo intermediates. (3) Particular Histidine (His) containing motifs occur in some Cu monooxygenase enzymes. Cu ion and Cu(I)/O2 reactivity studies will be developed with (i) His-Xaa-His ligands where the availability o ?N vs. ?N imidazole tautomeric positions as donors are to be systematically controlled via synthetic means. (ii) The 'histidine-brace' motif, Cu-chelation from a terminal His residue, will b examined for Cu ion and Cu(I)-O2 chemistries employing synthetically varied histamine-based ligands, (4) Short time-scale (ns, ?s) Cu(I)-O2 chemistry will be probed by laser photo-initiated O2-ejection from discrete Cun-O2 complexes. We will obtain kinetic-thermodynamic descriptions of systems having fast O2-to-Cu(I) binding to form one entity and then transforming to another. Also, these studies may help identify Cun- O2 excited states. (5) Advanced studies will focus on copper/O2/nitric-oxide interactions, following a new paradigm concerning the possible role of copper ion in the biological formation of the reactive nitrogen species peroxynitrite (-OON=O; PN). Cu-PN complexes will be investigated for their transformation to Cu-nitrate, vs Cu-nitrite + O2(g). An emphasis will be placed on Cu-PN reactivity with carbon dioxide, a biologically relevant substrate that enhances PN's damaging effects via formation of the carbonate radical anion and NO2 radical. Overall, the proposed studies will contribute to a broader understanding of copper biochemistry involving O2 and/or NO, activation of O2 and NOx in biology, and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.
The proposed studies contribute to a broader understanding of copper biochemistry, other metalloprotein (e.g., heme or non-heme iron) activation/reduction of O2 and NOx in biology and associated disease states. Potential long-term applications of this basic research include development of enzyme inhibitors and relevant disease therapeutic strategies.
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