Reactivity of Manganese and Iron Metalloenzyme Models

这项建议集中在过渡金属卟啉类化合物的合成和反应性。 旨在对血红素酶的结构和功能的关键方面进行建模。血红素酶的一个子集反应 与O2和/或相关小分子H_2O_2和O_2-，包括细胞色素P450(CYP)、双加氧酶 如色氨酸双加氧酶或吲哚胺双加氧酶，过氧化物酶，如氯过氧化物酶和 髓过氧化物酶、芳香族过氧化物酶、过氧化氢酶、血红素加氧酶和细胞色素C氧化酶。虽然 这些酶执行不同的关键功能，它们提出的作用机制有 多个中间体是共同的。这些中间体包括高价金属氧和金属羟基。 物种，如FeIV(O)(卟啉-自由基阳离子)(化合物-I)和FeIV(OH)(卟啉)(质子化) 化合物-II)，以及金属-氧物种，如FeIII(超氧)(卟啉)。这个 控制这些物种的产生、稳定性和反应性的因素在许多情况下仍然知之甚少。 这些物种被提议发挥关键作用的整体行动机制也是如此。这个 建议的努力集中在开发M=O、M-OH和M-O2中间体的合成卟啉类似物， 并研究了它们在氢原子转移(HAT)、质子耦合电子转移(PCET)、氧原子转移中的反应活性 转移(OAT)和反弹流程。以C-H键和O2为氧化剂的底物催化氧化 也将接受调查。这些模拟还将提供所需的光谱基准(RR、Mössbauer、 EPR，XAS)，用于与相关生物物种进行比较和鉴定。一种新系列的铁和铁 以考拉尔(Crl)和腐拉津(Cz)为配体合成了类锰卟啉配合物。这些 卟啉类化合物通过卟啉核的环收缩进行修饰，并被设计为 稳定金属氧物种，如高价M=O和M-OH络合物。在上一个资助期 我们的团队已经证明，Cz支架产生了具有生物相关性的新的M=O和M-OH络合物，并且 对这些体系的研究导致了关于氧化态、自旋态、配位 环境，以及近端和远端对HAT、PCET和OAT反应性的影响。新科罗尔和腐拉津 本建议书中将准备旨在解决两个主要目标的复合体1)答案 与血红素酶结构、功能和机制有关的基本问题和2)收获 关于过渡金属卟啉配合物的基本知识，用于设计和 新催化剂的合成。血红素酶对一系列疾病状态至关重要。新的 关于这些系统的作用机制所获得的知识应有助于发展 针对这些酶的新的治疗和/或诊断策略。

This proposal focuses on the synthesis and reactivity of transition metal porphyrinoid complexes that are designed to model key aspects of structure and function in heme enzymes. A subset of heme enzymes react with O2 and/or the related small molecules H2O2 and O2-, including Cytochrome P450 (CYP), dioxygenases such as tryptophan dioxygenase or indoleamine dioxygenase, peroxidases such as chloroperoxidase and myeloperoxidase, aromatic peroxygenase, catalases, heme oxygenases, and cytochrome c oxidase. Although these enzymes carry out a diverse array of critical functions, their proposed mechanisms of action have multiple intermediates in common. These intermediates include high-valent metal-oxo and metal-hydroxo species, such as FeIV(O)(porphyrin-radical-cation) (Compound-I) and FeIV(OH)(porphyrin) (protonated Compound-II) identified in CYP, as well as metal-dioxygen species such as FeIII(superoxo)(porphyrin). The factors that control the generation, stability, and reactivity of these species remains poorly understood in many cases, as do the overall mechanisms of action in which these species are proposed to play key roles. The proposed efforts focus on developing synthetic porphyrinoid analogs of M=O, M-OH, and M-O2 intermediates, and studying their reactivity in H-atom transfer (HAT), proton-coupled electron-transfer (PCET), O-atom transfer (OAT), and rebound processes. Catalytic oxidations of substrates with C-H bonds and O2 as oxidant will also be investigated. These analogs will also provide needed spectroscopic benchmarks (rR, Mössbauer, EPR, XAS) for comparison with, and identification of, the relevant biological species. A new series of Fe and Mn porphyrinoid complexes will be synthesized with corrole (Crl) and corrolazine (Cz) ligands. These porphyrinoid compounds are modified by ring contraction of the porphyrin nucleus, and are designed to stabilize metal-oxygen species such as high-valent M=O and M-OH complexes. In the previous funding period our group has shown that the Cz scaffold yields new M=O and M-OH complexes of biological relevance, and the study of these systems led to discoveries regarding the influence of oxidation state, spin state, coordination environment, and proximal and distal effects on HAT, PCET, and OAT reactivity. New corrole and corrolazine complexes will be prepared in this proposal that are designed to address two main goals 1) answer fundamental questions related to heme enzyme structure, function and mechanism and 2) gain fundamental knowledge regarding transition metal porphyrinoid complexes for the design and synthesis of new catalysts. Heme enzymes are of central importance to a range of disease states. The new knowledge to be gained regarding the mechanisms of action of these systems should help in the development of novel therapeutic and/or diagnostic strategies that target these enzymes.