Bioinorganic Copper Coordination Chemistry

描述（由申请人提供）：拟议研究的目标是进一步发展铜配位化学的基本方面，其在二氧（O2）和氮氧化物（NOx）的生化处理中的重要作用。关于铜(l)/O2相互作用，O2-加合物形成的动力学和能量学，以及关于结构，相关光谱，O-O键裂解（即O2-活化）和底物氧化化学的许多问题仍然存在。这些也可能与氧化应激的情况有关，例如在阿尔茨海默病等神经系统疾病中。铜- nox的研究与亚硝酸盐和一氧化二氮（N2O）还原酶的活性位点化学有关，以及铜离子在一氧化二氮（NO）生物化学中的可能作用，包括无-过氧亚硝酸盐（O=NOO~）化学和氧化（和/或硝化）应激中O2的中介作用。研究方法分为子项目，沿着不同的主题或化学系统。这些研究包括(1)O2和一氧化碳（CO，作为O2替代物）与四齿配体Cu(l)螯合物结合动力学和热力学的研究，(2)关键配体-Cu2+(O2-)（超氧化物）溶剂氢键和光化学的研究，(3)涉及氢原子转移化学的配体-Cu2+(O2-)底物反应的机理细节的主要研究，(4)包括硫醚供体在内的新型四齿配体-Cu配合物的研究。(5)瞬态吸收光谱检测先前未观察到的Cu/O2 =1:1加合物，并阐明其动力学-热力学和光谱学，采用高活性的三齿配体Cu配合物体系；(6)铜离子的配位、结构和结构的研究；与组氨酸-组氨酸肽片段（铜生物化学中的新结合基序）的结合和化学反应性，强调了先前未研究的HisHis的铜(1)配位化学和已知的阿尔茨海默病相关淀粉样蛋白的金属结合部分（残基6-14）。(7) Cu-硫化物化学的阐述，包括与氧化亚氮还原酶活性位点相关的新簇化合物的生成和表征，特别强调了这些复合物还原激活N2O的能力；(8)研究了配体Cu+与NO和O2的反应，从而导致过氧亚硝酸盐衍生的化学反应。拟议的研究有助于更广泛地了解铜的生物化学，其他金属蛋白（例如血红素或非血红素铁）在生物学和相关疾病状态中对O2和NOx的激活/还原。这项基础研究的潜在长期应用包括开发酶抑制剂和相关疾病治疗策略。

DESCRIPTION (provided by applicant): The goal of the proposed research is to further develop fundamental aspects of copper coordination chemistry relevant to its essential role in the biochemical processing of dioxygen (O2) and nitrogen oxides (NOx). Many questions remain concerning copper(l)/O2 interactions, dynamics & energetics of O2-adduct formation, as well as questions concerning structure, associated spectroscopy, O-O bond cleavage (i.e., O2- activation) and substrate oxidation chemistries. These may also be relevant to situations of oxidative stress, e.g., in neurological disorders such as Alzheimer's disease. Copper-NOx investigations are relevant to the active site chemistry in nitrite and nitrous oxide (N2O) reductases, and to the possible role of copper ion in nitrogen monoxide ("NO) biochemistry, including mediation of O2 with -NO peroxynitrite (O=NOO~) chemistry and oxidative (and/or nitrative) stress. The research methods divide into sub-projects, directed along various themes or chemical systems. These include (1) study of O2 and carbon monoxide (CO, as O2-surrogate) kinetics and thermodynamics of binding to tetradentate ligand Cu(l)-chelates, (2) study of key ligand- Cu2+(O2-) (superoxide) solvent hydrogen bonding and photochemistry, (3) a major effort to unravel mechanistic details of ligand-Cu2+(O2-) substrate reactivity involving hydrogen-atom transfer chemistry, (4) study of new tetradentate ligand-Cu complexes including with thioether donors, of relevance to certain Cu- monooxygenases, emphasizing O2 & CO binding kinetics-thermodynamics and structural-spectroscopic comparisons to other systems, (5) transient absorption spectroscopic detection of previously unobserved primary Cu/O2 =1:1 adducts and elucidation of their kinetics-thermodynamics and spectroscopy, employing highly reactive tridentate ligand Cu complex systems, (6) investigation of copper ion complexation, structure, binding and chemical reactivity with histidine-histidine peptide moieties (novel binding motifs in copper biochemistry), emphasizing previously un-researched copper(l) coordination chemistry of HisHis and the known metal binding portion (residues 6-14) of the Alzheimer's disease associated amyloid ??peptide, (7) elaboration of Cu-sulfide chemistry, including generation and characterization of new cluster compounds relevant to the active site of nitrous oxide reductase, with additional emphasis placed on the complexes' ability to reductively activate N2O, and (8) investigation of ligand Cu+ reactions with NO and O2, leading to peroxynitrite-derived chemistry. 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.