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发展， 在单加氧酶的活性位点内发现的性质，以探测金属介导的 分子氧利用的两个关键设计特征是分子内氢键（H-键）的结合 次级配位圈内的网络和初级配位圈内的氧化还原活性配体的使用 协调领域。将这些特征耦合到单个配体系统中代表了分子生物学的进步。 设计应允许分离模拟中间体结构的Fe-氧代物质 P450在O2活化过程中产生。该方法利用具有H键的三齿氧化还原活性配体 位于次级配位层内的受体。该方法的一个优点是， 另外的配体可以容易地与金属中心配位;因此，可以 制备、表征和筛选功能。特别地，具有轴向硫醇盐供体的铁络合物是 提出，将模拟许多结构特征内发现的活性位点的细胞色素 P450单加氧酶。与这些酶类似，预期所提出的络合物中的金属离子 结合并活化二氧（O2）以形成H-键稳定的过氧（O22-）或氧代（O2-）单元， 使底物的C-H键官能化。因此，与O2和烃底物的反应性研究是 还提出了其中所产生的产品将使用光谱和计算的特点， 技术，包括紫外可见光谱，EPR，穆斯堡尔，FTIR光谱和密度泛函理论。 这些研究有望加深对单加氧酶活性的生物化学的理解， 位点以及富含稀土的金属如何能够有效地活化惰性基质的C-H键。