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Developing Coordination Complexes with Redox-Active Ligands into Anti-Oxidants and MRI Contrast Agent Sensors for Reactive Oxygen Species

将具有氧化还原活性配体的配位络合物开发成抗氧化剂和活性氧的 MRI 造影剂传感器

基本信息

批准号：
1662875
负责人：
Christian Goldsmith
金额：
$ 42万
依托单位：
Auburn University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2017
资助国家：
美国
起止时间：
2017-08-01 至 2021-07-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1662875&HistoricalAwards=false
关键词：
Developing Coordination Complexes Redox Active

项目摘要

In this project, funded by the Chemical Structure, Dynamic & Mechanism B Program of the Chemistry Division, Professor Christian R. Goldsmith of the Department of Chemistry and Biochemistry at Auburn University is developing new transition metal complexes capable of detecting and/or degrading reactive oxygen species. The goal of this research is to develop redox-responsive contrast agents for magnetic resonance imaging (MRI) and functional mimics of superoxide dismutase enzymes. Given the involvement of reactive oxygen species in cardiovascular, neurological, and inflammatory disease, these complexes could form the bases for improved diagnosis and treatment options for a wide range of health conditions. The project is at the interface of inorganic chemistry, organic chemistry, and biochemistry. As such, it provides excellent training for undergraduate and graduate students. The project also sponsors research seminars at primarily undergraduate institutions in the east Alabama area and enables their students to participate in cutting-edge scientific research. Mn(II) complexes with quinol-containing polydentate ligands have recently been found to display both enhanced T1-weighted relaxivity (r1) in response to H2O2 and the ability to catalytically degrade superoxide. Upon reaction with H2O2, the metal-bound quinols are oxidized to para-quinones, which bind less avidly to the metal centers. Oxidation therefore renders the polydentate ligands less highly coordinating, allowing for increased aquation and r1. The primary drawback is that much of the Mn(II) is likely released upon oxidation, which both limits the r1 response and poses a hazard to cells. This project attempts to address the stability issue in two different ways. First, more tightly binding ligands that feature carboxylates instead of pyridines are explored; these are anticipated to bind to the Mn(II) ions more tightly than the first generation ligands while improving upon the spectroscopic response. Second, Ni(II) and Co(II) complexes with both the first and second generation ligands will be prepared and assessed as chemical exchange saturation transfer (CEST)-derived MRI contrast agents. Ni(II) and Co(II) bind to ligands much more strongly than Mn(II), and a CEST-based mechanism could allow greater sensitivity to H2O2 than T1-weighted imaging. The project also explores the superoxide dismutase (SOD) activity of the Mn(II) complexes as well as those of their Ni(II), Co(II), and Zn(II) analogs. The Zn(II) complexes thus far appear to be equivalent anti-oxidants to the Mn(II) compounds, and the proposed work will determine whether and how SOD activity can be obtained using a redox-active ligand, rather than a metal ion, as the relevant redox partner.

奥本大学化学与生物化学系的Christian R. Goldsmith教授在化学结构、动态与机制B项目的资助下，正在开发能够检测和/或降解活性氧的新型过渡金属配合物。本研究的目的是开发用于磁共振成像（MRI）和超氧化物歧化酶功能模拟的氧化还原反应造影剂。考虑到活性氧在心血管、神经和炎症疾病中的作用，这些复合物可以为改善各种健康状况的诊断和治疗选择奠定基础。本课题是无机化学、有机化学和生物化学的交叉学科。因此，它为本科生和研究生提供了良好的培训。该项目还在阿拉巴马东部地区的主要本科院校举办研究研讨会，使学生能够参与尖端科学研究。最近发现含有喹啉的多齿配体的Mn（II）配合物在H2O2作用下表现出增强的t1加权弛豫度（r1）和催化降解超氧化物的能力。与H2O2反应后，金属结合的喹啉被氧化为对醌，对醌与金属中心的结合不那么紧密。因此，氧化使多齿配体的配位不那么高，允许增加水和r1。主要缺点是大部分锰（II）可能在氧化时释放，这既限制了r1反应，又对细胞构成危害。该项目试图以两种不同的方式解决稳定性问题。首先，研究人员探索了以羧酸盐代替吡啶的更紧密结合的配体；预计这些与Mn（II）离子的结合比第一代配体更紧密，同时改善了光谱响应。其次，制备具有第一代和第二代配体的Ni（II）和Co（II）配合物，并将其作为化学交换饱和转移（CEST）衍生的MRI造影剂进行评估。Ni（II）和Co（II）与配体的结合比Mn（II）强得多，基于cest的机制可以比t1加权成像对H2O2具有更高的灵敏度。该项目还探讨了Mn（II）配合物及其Ni(II), Co（II）和Zn（II）类似物的超氧化物歧化酶（SOD）活性。迄今为止，锌（II）配合物似乎与锰（II）化合物具有相同的抗氧化剂作用，所提出的工作将确定是否以及如何使用氧化还原活性配体而不是金属离子作为相关的氧化还原伙伴来获得SOD活性。

项目成果

期刊论文数量（7）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

An overly anionic metal coordination environment eliminates the T-weighted response of quinol-containing MRI contrast agent sensors to H2O2

过度阴离子金属配位环境消除了含对苯二酚的 MRI 造影剂传感器对 H2O2 的 T 加权响应

DOI：
10.1016/j.ica.2019.119045
发表时间：
2019
期刊：
Inorganica Chimica Acta
影响因子：
2.8
作者：
Hutchinson, Tessa E.;Bashir, Adam;Yu, Meng;Beyers, Ronald J.;Goldsmith, Christian R.
通讯作者：
Goldsmith, Christian R.

Diquinol Functionality Boosts the Superoxide Dismutase Mimicry of a Zn(II) Complex with a Redox-Active Ligand while Maintaining Catalyst Stability and Enhanced Activity in Phosphate Solution

二喹啉功能可增强具有氧化还原活性配体的 Zn(II) 络合物的超氧化物歧化酶模拟，同时保持催化剂稳定性并增强磷酸盐溶液中的活性

DOI：
10.1021/acs.inorgchem.2c03256
发表时间：
2022
期刊：
Inorganic Chemistry
影响因子：
4.6
作者：
Moore, Jamonica L.;Oppelt, Julian;Senft, Laura;Franke, Alicja;Scheitler, Andreas;Dukes, Meghan W.;Alix, Haley B.;Saunders, Alexander C.;Karbalaei, Sana;Schwartz, Dean D.
通讯作者：
Schwartz, Dean D.

Co(II) Complex with a Covalently Attached Pendent Quinol Selectively Reduces O 2 to H 2 O

带有共价连接的对苯二酚侧链的 Co(II) 络合物选择性地将 O 2 还原为 H 2 O