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的配位化学，与其在O2和氮氧化物(NOx)的生化处理中的基本作用相关。研究子项目包括：(1)原生铜(I)-O2加合物的详细研究。对于几种铜(II)(O2·-)物种，我们将考察它们的质子化还原化学，以得到铜(II)-(氢)过氧化物系。将改变酸和还原剂，并研究动力学，以提供关于电子转移的见解，可能涉及质子耦合电子转移(PCET)。还将从力学角度研究铜(II)(O2·-)与C-H或O-H底物的反应能力，以确定它们的氧化能力。具有一个硫醚配体给体的铜(II)(O2·-)物种也将被包括在内；我们将探索O2-化学涉及蛋氨酸硫自由基阳离子形成的可能性，这可能是该领域的一种新范式。(2)一组特定的具有不同R(=H，烷基或酰基)的铜(II)2-OOR络合物将受到不同pKa值的酸的影响，并研究 它们的O-O还原裂解化学。将进行动力学研究、同位素效应测定和产物分析，以阐明O-O裂解、均解或异解的机理。我们希望能鉴定出高价铜氧中间体。(3)某些铜单加氧酶中存在特殊的组氨酸(His)基序。铜离子和铜(I)/O2的反应性研究将用(I)His-Xaa-His配体进行，其中N和N咪唑作为供体的互变异构体的可用性将通过合成手段系统地控制。(Ii)将利用合成的各种组胺类配体来研究铜离子和铜(I)-O2的化学作用；(4)将用激光引发的短时间尺度(ns，S)来探索短时间尺度的铜(I)-O2化学。 氧从离散的CuN-O2络合物中射出。我们将获得具有快速O2-to-Cu(I)结合的体系的动力学-热力学描述，以形成一个实体，然后转变为另一个实体。此外，这些研究可能有助于确定CuN-O2的激发态。(5)高级研究将侧重于铜/O2/一氧化氮-氧化物的相互作用，遵循关于铜离子在活性氮物种过氧亚硝酸盐(-Oon=O；Pn)的生物形成中可能扮演的角色的新范式。将研究铜-PN络合物转化为铜-硝酸盐，而不是铜-亚硝酸盐+O2(G)。重点将放在铜-净光合酶与二氧化碳的反应性上，二氧化碳是一种生物相关的底物，通过形成碳酸盐自由基阴离子和NO2自由基来增强净光合酶的破坏性作用。总体而言，拟议的研究将有助于更广泛地了解铜的生物化学，包括O2和/或NO，O2和NOx在生物学中的激活，以及相关的疾病状态。这项基础研究的潜在长期应用包括开发酶抑制剂和相关的疾病治疗策略。

 DESCRIPTION (provided by applicant): 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.