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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.

项目总结