Integrated Control of the Primary and Secondary Coordination Spheres in Synthetic Monooxygenase Mimics: Probing Dioxygen Activation at a Single Metal Site.

合成单加氧酶模拟物中初级和次级配位球的集成控制：探测单个金属位点的双氧活化。

• 批准号: 9328564
• 负责人: Justin Bogart
• 金额: $ 5.67万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9328564
• 关键词: Active Sites; Affect; Binding; Biochemistry; Bioinorganic Chemistry; Biological; Biological Models; Chemistry; Complex; Computational Technique; Coupling; Cysteine; Cytochrome P450; Development; Dioxygen; Distal; Electron Spin Resonance Spectroscopy; Electrons; Environment; Enzymes; Event; Family; Goals; Hydrocarbons; Hydrogen Bonding; Ions; Iron; Laboratories; Lead; Ligands; Mediating; Metalloproteins; Metals; Mixed Function Oxygenases; Modeling; Molecular; Mononuclear; Mossbauer Spectroscopy; Nature; Optics; Oxidation-Reduction; Oxygen; Periodicity; Phase; Planet Earth; Porphyrins; Positioning Attribute; Preparation; Property; Proteins; Research; Role; Site; Spectroscopy, Fourier Transform Infrared; Steroid biosynthesis; Structure; Structure-Activity Relationship; Sulfonamides; Synthesis Chemistry; System; Variant; catalyst; density; design; drug metabolism; experience; heme a; insight; metal complex; oxidation; success; theories

Project Summary. The proposed research plan describes the development of synthetic systems that emulate the properties found within the active sites of monooxyenases in order to probe metal-mediated activation of dioxygen. Two key design features utilized are incorporation of intramolecular hydrogen bonding (H-bond) networks within the secondary coordination sphere and the use of redox-active ligands within the primary coordination sphere. Coupling these features into a single ligand system represents an advance in molecular design that should allow for the isolation of Fe–oxo species that mimic the structures of the intermediates produced by P450 during activation of O2. This approach utilizes tridentate redox-active ligands with H-bond acceptors positioned within the secondary coordination sphere. One advantage of the approach is that additional ligands can be readily coordinated to the metal center; thus, several different variants can be prepared, characterized, and screened for function. In particular, iron complexes with axial thiolate donors are proposed that would simulate many of the structural features found within the active sites of the cyctochrome P450 monooxygenases. Similar to these enzymes, the metal ions in the proposed complexes are expected to bind and activate dioxygen (O2) to form H-bond stabilized peroxo (O22–) or oxo (O2–) units capable of functionalizing C–H bonds of substrates. Therefore, reactivity studies with O2 and hydrocarbon substrates are also proposed in which the generated products will be characterized using spectroscopic and computational techniques that include UV-vis, EPR, Mössbauer, and FTIR spectroscopies and density functional theory. These studies are expected to lead to a greater understanding of the biochemistries of monooxygenase active sites and how earth abundant metals are capable of efficiently activating C–H bonds of inert substrates.

项目摘要。拟议的研究计划描述了模拟合成系统的开发。 在单加氧酶活性位点内发现的特性，以探测金属介导的激活 利用的两个关键设计特征是分子内氢键（H 键）的结合。 次级配位层内的网络以及初级配位层内氧化还原活性配体的使用 将这些特征耦合到单个配体系统中代表了分子的进步。 设计应允许分离模拟中间体结构的 Fe-oxo 物质 该方法利用具有氢键的三齿氧化还原活性配体。 该方法的一个优点是，受体位于次级协调范围内。 额外的配体可以很容易地与金属中心配位；因此，可以有几种不同的变体 特别是具有轴向硫醇盐供体的铁络合物的制备、表征和功能筛选。 提出将模拟细胞色素活性位点内发现的许多结构特征 P450 单加氧酶与这些酶类似，预计复合物中的金属离子 结合并激活双氧 (O2)，形成氢键稳定的过氧 (O22–) 或氧 (O2–) 单元，能够 因此，O2 和碳氢化合物底物的反应性研究正在进行中。 还建议使用光谱和计算来表征生成的产品 技术包括 UV-vis、EPR、Mössbauer、FTIR 光谱和密度泛函理论。 这些研究预计将有助于人们更好地了解单加氧酶活性的生物化学 位点以及地球上丰富的金属如何能够有效地激活惰性基质的 C-H 键。