Bioinorganic Copper Coordination Chemistry

 描述（由申请人提供）：拟议研究的目标是进一步开发铜配位化学的各个方面，这些方面与其在O2和氮氧化物（NOx）的生化处理中的重要作用有关。研究子项目包括：（1）初级铜（I）-O_2加合物的详细研究。对于几种Cu（II）（O2·-）物种，我们将研究它们的质子化还原化学，得到Cu（II）-（氢）过氧化物。酸和还原剂将是不同的和动力学研究，提供有关电子转移的见解，可能涉及质子耦合电子转移（PCET）。Cu（II）（O2·-）配合物与C-H或O-H底物的反应性也将进行机械研究，以确定其氧化能力。Cu（II）（O2·-）物种与一个硫醚配体供体也将包括在内，我们将探讨的可能性，O2-化学涉及蛋氨酸硫自由基阳离子的形成，在该领域可能的新范例。(2)一组特定的Cu（II）2-OOR络合物，具有不同的R（= H、烷基或酰基），将经受不同pKa值的酸，并研究 它们的O-O还原裂解化学。动力学研究、同位素效应测定和产物分析将用于阐明O-O裂解、均裂或异裂的机理。我们希望能鉴定出高价铜氧中间体。(3)特定的含组氨酸（His）基序出现在一些Cu单加氧酶中。Cu离子和Cu（I）/O2反应性研究将使用（i）His-Xaa-His配体进行，其中通过合成方法系统地控制作为供体的N-咪唑与N-咪唑互变异构位置的可用性。(ii)利用人工合成的不同组胺配体，对"组氨酸-支撑"基序，即末端His残基的Cu螯合作用，进行了Cu离子和Cu（I）-O2化学反应的B研究。（4）采用激光光引发的方法， 从离散的Cun-O2复合物中排出O2。我们将获得系统的动力学-热力学描述具有快速O2-到-Cu（I）结合形成一个实体，然后转化为另一个。此外，这些研究可能有助于识别Cun-O2激发态。(5)先进的研究将集中在铜/O2/氮氧化物的相互作用，以下一个新的范例，关于铜离子在生物形成的活性氮物种过氧亚硝酸盐（-OON = O; PN）的可能作用。将研究Cu-PN络合物转化为Cu-硝酸盐，与Cu-亚硝酸盐+O2（g）。重点将放在Cu-PN与二氧化碳的反应性上，二氧化碳是一种生物相关的底物，通过形成碳酸根阴离子和NO2自由基来增强PN的破坏作用。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，涉及O2和/或NO，在生物学中的O2和NOx的活化，以及相关的疾病状态。这项基础研究的潜在长期应用包括酶抑制剂和相关疾病治疗策略的开发。

 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.