Understanding How Thiolates Promote Dioxygen Chemistry

了解硫醇盐如何促进双氧化学

基本信息

批准号：
10444825
负责人：
Julia A Kovacs
金额：
$ 42.82万
依托单位：
UNIVERSITY OF WASHINGTON
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-05-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10444825
关键词：
Acute Affect Amines Anabolism Azides Bacteria Bacterial Infections Binding Binding Sites Bond-It Cancerous Cations Chemistry Complex Coupled Crystallization Cysteine Cysteine dioxygenase Deuterium Dioxygen Electrochemistry Electron Transport Enzymes Freezing Goals Hydrogen Hydrogen Bonding Hydrogenase In Situ Iron Isomerism Isotopes Kinetics Ligands Liquid substance Measures Modeling Monitor Monobactams Mossbauer Spectroscopy Neoplasm Metastasis Nitrogen Oxidation-Reduction Oxygen Pathway interactions Play Positioning Attribute Production Protons Reaction Reporting Resistance Source Spectrum Analysis Sulfur Testing Time Tumor Suppressor Proteins Vertebral column Work absorption analog antineoplastic antibiotics aqueous beta-Lactams carbene cold temperature cryogenics density enzyme mechanism experimental study fighting follow-up instrument isopenicillin N nervous system disorder novel anticancer drug oxidation prevent scaffold small molecule time interval tumor vibration weapons

项目摘要

Project Summary Cysteinate-ligated non-heme iron superoxo intermediates (RS-FeIII-O2•–) play a key role in the mechanisms of isopenicillin N-synthase (IPNS) and cysteine dioxygenase (CDO). The former provides our only source of β- lactam antibiotics, and the latter is known to prevent metastases of cancerous tumors and neurological disorders. Very little is known about the mechanisms of these reactions, the understanding of which will facilitate the synthesis of new anticancer drugs and antibiotics to which bacteria are not yet resistant. Very few well- characterized FeIII-O2•– compounds have been reported, and only two include a thiolate in the coordination sphere. Our group reported the first and only example of an RS-FeIII-O2•– capable of cleaving strong C-H bonds on par with cysteine β-C-H bond cleaved by IPNS. The goal of the work proposed herein will be to determine whether ligand constraints can be used to alter the reaction pathway of our RS-FeIII-O2•– from that of IPNS to that of CDO. We will incorporate β-hydrogens into our aliphatic thiolate ligand and determine whether intramolecular β C-H bond cleavage occurs, and β-deuteriums to see if that stabilizes the FeIII-O2•–, and if so, determine the kinetic isotope effect to provide additional support for intramolecular β-C-H bond cleavage. We will determine whether the trans thiolate influences the potency of our RS-FeIII-O2•– with respect to C-H bond cleavage by exploring the O2 chemistry of our mixed alkoxide/thiolate-ligated FeII complex. We will use Mossbauer spectroscopy and spectro-electrochemistry to provide evidence for the involvement of proton coupled electron transfer in the conversion of our putative high valent O=(R)S-FeIV=O to the corresponding O=(R)S-FeIII-OH and obtain the FeIIIO–H bond strength from the slope of the Pourbaix (pH vs E1/2) diagram. We will also examine the effects of redox inactive Lewis acidic cations and protons on the ability of our crystallographically characterized cis RS-FeIV=O to cleave strong C-H bonds, and determine how the thiolate affects this reactivity by synthesizing the corresponding cis RO-FeIV=O compound and examining pH-dependent redox potentials using spectro- electrochemistry and comparing the O–H bond strengths, obtained from the slope of the Pourbaix (pH vs E1/2) diagram, for cis RO-FeIII-OH versus cis RS-FeIII-OH. We will insert a methylene group into the ligand scaffold of our crystallographically characterized cis RS-FeIV=O to determine whether ligand constraints prevent intramolecular oxo atom transfer. Lastly, we will determine whether the synergistic interaction between a 𝛑- donating thiolate and 𝛑-accepting CO ligands facilitates hydrogenase (H2-ase) promoted H2 production and H2 cleavage.

项目摘要半胱氨酸的非血红素铁超氧中间体（RS-FEIIII-O2• - ）在机制中起关键作用亚匹热蛋白N-合酶（IPNS）和半胱氨酸二氧酶（CDO）。前者提供了我们唯一的β-来源已知lactam抗生素和后者可以预防取消肿瘤和神经系统疾病的转移。关于这些反应的机制知之甚少，对这些反应的理解将有助于尚未抗性的新抗癌药物和抗生素的合成。很少据报道了FEIIII-O2• - 已经报道了化合物，只有两种包括硫醇酸盐领域。我们的小组报告了RS-FEIIII-O2的第一个也是唯一的例子• - 能够切割强C-H键与半胱氨酸β-C-H键相当，由IPN裂解。本文提出的工作的目的是确定是否可以使用配体约束来改变我们的RS-FEIIII-O2• - 从IPN的反应途径 CDO。我们将将β-糖基因掺入脂肪族硫醇酸盐配体中，并确定分子内分子是否发生βC-H键裂解，并查看β-蛋白酶是否稳定了FeIIII-O2• - ，如果是的，请确定动力学同位素效应为分子内β-C-H键裂解提供额外的支持。我们将确定反硫醇是否会影响我们的RS-FEIIII-O2• - 关于C-H键的裂解探索我们混合的烷氧化物/硫醇酸酯绑扎FEII复合物的O2化学。我们将使用Mossbauer 光谱和光谱电化学，提供证据证明质子耦合电子的参与在我们推定的高价值o =（r）s-feiv = o的转换中转移到相应的o =（r）s-feiii-oh，并且从Pourbaix（pH VS E1/2）图的斜率获得FEIIIO -H键强度。我们还将检查氧化还原活性刘易斯酸性阳离子和质子对我们晶体学表征的能力的影响顺式rs-feiv = o清除较强的C-H键，并确定硫醇如何通过合成来影响这种反应性相应的顺式ro-feiv = o化合物并使用spectro- 电化学和比较从Pourbaix的斜率获得的O – H键强度（pH vs e1/2）图，用于顺式RO-FEIII-OH与顺式RS-FEIII-OH。我们将将亚甲基插入我们的晶体学表征顺式rs-feiv = o，以确定配体约束是否阻止分子内氧原子转移。最后，我们将确定𝛑-之间的协同相互作用是否捐赠硫醇酸盐和𝛑接受配体有助于氢化酶（H2-ase）促进H2的产生和H2 乳沟。