Reactivity of Manganese and Iron Metalloenzyme Models

该建议的重点是过渡金属卟啉配合物的合成和反应性， 旨在模拟血红素酶的结构和功能的关键方面。血红素酶的一个子集 与O2和/或相关的小分子H2O2和O2-，包括细胞色素P450（CYP）， 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， 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 这些酶执行各种各样的关键功能，它们提出的作用机制有 多个中间体的共同点。这些中间体包括高价金属氧代和金属氢氧化物 例如FeIV（O）（卟啉-自由基-阳离子）（化合物-I）和FeIV（OH）（卟啉）（质子化的 化合物-II），以及金属-双氧物质如Fe III（超氧）（卟啉）。的 控制这些物种的产生、稳定性和反应性的因素在许多国家仍然知之甚少。 这些物种被提议在其中发挥关键作用的总体作用机制也是如此。的 所提出的努力集中于开发M = O、M-OH和M-O2中间体的合成类卟啉类似物， 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（O-atom transfer，O-atom transfer）等反应中的活性 转移（OAT）和反弹过程。以O2为氧化剂的C-H键催化氧化底物 也将被调查。这些类似物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。一个新的系列的铁和 本文以吡咯（Crl）和甲苯胺（Cz）为配体合成了锰卟啉配合物。这些 类卟啉化合物通过卟啉核的缩环来修饰，并被设计成 稳定金属-氧物种如高价M = O和M-OH络合物。在上一个供资期间， 我们的小组已经表明，Cz支架产生了新的生物相关的M = O和M-OH复合物， 对这些系统的研究导致了关于氧化态、自旋态、配位的影响的发现。 环境以及对HAT、PCET和OAT反应性的近端和远端效应。新可咯和可咯嗪 本提案中将准备一个综合体，旨在解决两个主要目标：1）回答 有关血红素酶结构、功能和机制的基本问题; 2）获得 关于过渡金属卟啉配合物的设计和 新催化剂的合成。血红素酶对一系列疾病状态至关重要。新 关于这些系统的作用机制的知识应该有助于开发 针对这些酶的新型治疗和/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.