The long term objective of the proposed research is the development of the fundamental coordination chemistry of copper ion as it pertains to the active site chemistry of proteins involved in O2-transport, O2- activation (e.g., monooxygenation, N-dealkylation) and O2-reduction. Through detailed studies of chemical model systems, a reasonable basis for hypothesis of biological structure and competency of intermediates can be made. There exists a paucity of information about Cu(I) coordination chemistry, and its reactions with O2/substrate. Our interests are in functional modeling, i.e., reactions of CuI/O2 and CuI/O2/substrate. The structures, spectroscopy and reactivity of possible intermediates such as Cu-O2-Cu, Cu-OOH, Cu-O-Cu and Cu-O are poorly understood. Systematic investigations using model compounds with varied, but known structure, ligation and associated CuII/CuI redox potential can lead to a better understanding of the biological transformations. The proposed research is divided into sub-projects, directed along various themes, questions, or chemical systems. We plan to study: (1) Cu-pterin interactions, to help elucidate the active site chemistry of Cu-phenylalanine hydroxylase. Chelating pterins will be used to study Cu/O2 reactions with reduced pterins and substrates. (2) Chemistry with tripodal tetradentate ligands, including dinucleating versions. Both Cu/O2 1:1 and 2:1 adducts should form and comparisons of structure, kinetics/thermodynamics and reactivity will provide fundamental information. (3) L2CuI/O2 + L' and LnCuI-X (X = CO, CN-, RNC, acetylene) chemistry with L as a biologically 'relevant' unidentate imidazole ligand. The latter compounds will help in developing spectroscopic probes for protein reduced Cu(I) ion. (4) The chemistry of side-on bound peroxo dinuclear complexes. Modified ligands will help probe structure and reactivity of these species, which are capable of effecting arene hydroxylation reactions. In addition to studies with 'endogenous' substrates, we will develop CuI/O2 chemistry using organic receptors for 'exogenous' substrates, such as cyclodextrins and those based on a diphenylglycoluril building block. (5) The chemistry of unsymmetrical dinuclear complexes will be developed. This is relevant to a number of Cu proteins, where one Cu ion (or cofactor) passes electrons to another which effects O2/substrate reactions. (6) Hydroperoxide-Cu interactions, which are involved in proteins such as dopamine b-hydroxylase and others. We will also investigate and compare structure, spectroscopy and reactivity of systems which are 'reductively activated', i.e., with Cu(I) complex reactions with ROOH. (7) Oxidative N-dealkylation chemistry using Cu-ligand systems observed to undergo such reactions; structures of intermediates and mechanism will be determined. (8) The chemistry of tri- and tetranuclear Cu complexes and their O2 reactions; Cu clusters occur in laccase & ascorbate oxidase and possibly in Cu methane monooxygenase. (9) O2-binding and reduction chemistry at porphyrin-Fe/Cu complexes, as structural/functional models for reactions occurring in cytochrome c oxidase.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Method to Extend Research in Time (MERIT) Award (R37)
Project #
4R37GM028962-18
Application #
2394564
Study Section
Special Emphasis Panel (NSS)
Project Start
1990-04-01
Project End
2003-03-31
Budget Start
1998-04-01
Budget End
1999-03-31
Support Year
18
Fiscal Year
1998
Total Cost
Indirect Cost
Name
Johns Hopkins University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
045911138
City
Baltimore
State
MD
Country
United States
Zip Code
21218
Bhadra, Mayukh; Lee, Jung Yoon C; Cowley, Ryan E et al. (2018) Intramolecular Hydrogen Bonding Enhances Stability and Reactivity of Mononuclear Cupric Superoxide Complexes. J Am Chem Soc 140:9042-9045
López, Isidoro; Cao, Rui; Quist, David A et al. (2017) Direct Determination of Electron-Transfer Properties of Dicopper-Bound Reduced Dioxygen Species by a Cryo-Spectroelectrochemical Approach. Chemistry 23:18314-18319
Cao, Rui; Elrod, Lee Taylor; Lehane, Ryan L et al. (2016) A Peroxynitrite Dicopper Complex: Formation via Cu-NO and Cu-O2 Intermediates and Reactivity via O-O Cleavage Chemistry. J Am Chem Soc 138:16148-16158
Liu, Jeffrey J; Diaz, Daniel E; Quist, David A et al. (2016) Copper(I)-Dioxygen Adducts and Copper Enzyme Mechanisms. Isr J Chem 56:9-10
Garcia-Bosch, Isaac; Cowley, Ryan E; Díaz, Daniel E et al. (2016) Dioxygen Activation by a Macrocyclic Copper Complex Leads to a Cu2O2 Core with Unexpected Structure and Reactivity. Chemistry 22:5133-7
Cao, Rui; Saracini, Claudio; Ginsbach, Jake W et al. (2016) Peroxo and Superoxo Moieties Bound to Copper Ion: Electron-Transfer Equilibrium with a Small Reorganization Energy. J Am Chem Soc 138:7055-66
Kim, Sunghee; Lee, Jung Yoon; Cowley, Ryan E et al. (2015) A N3S(thioether)-ligated Cu(II)-superoxo with enhanced reactivity. J Am Chem Soc 137:2796-9
Lee, Jung Yoon; Karlin, Kenneth D (2015) Elaboration of copper-oxygen mediated C-H activation chemistry in consideration of future fuel and feedstock generation. Curr Opin Chem Biol 25:184-93
Kim, Sunghee; Ginsbach, Jake W; Lee, Jung Yoon et al. (2015) Amine oxidative N-dealkylation via cupric hydroperoxide Cu-OOH homolytic cleavage followed by site-specific fenton chemistry. J Am Chem Soc 137:2867-74
Kim, Sunghee; Ginsbach, Jake W; Billah, A Imtiaz et al. (2014) Tuning of the copper-thioether bond in tetradentate N?S(thioether) ligands; O-O bond reductive cleavage via a [Cu(II)?(?-1,2-peroxo)]²?/[Cu(III)?(?-oxo)?]²? equilibrium. J Am Chem Soc 136:8063-71

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