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

本课题由化学系化学结构与动力学机制B项目资助，由中国科学院化学与物理研究所的Christian R.奥本大学化学和生物化学系的金匠正在开发能够检测和/或降解活性氧的新型过渡金属络合物。本研究的目的是开发磁共振成像（MRI）和超氧化物歧化酶的功能模拟物的氧化还原反应造影剂。鉴于活性氧参与心血管、神经和炎症疾病，这些复合物可以为改善各种健康状况的诊断和治疗方案奠定基础。该项目是在无机化学，有机化学和生物化学的接口。因此，它为本科生和研究生提供了出色的培训。该项目还在东亚拉巴马地区的主要本科院校赞助研究研讨会，使学生能够参与尖端科学研究。锰（II）配合物与含喹啉的多齿配体最近被发现显示增强T1加权弛豫（R1）响应于H2 O2和催化降解超氧化物的能力。在与H2 O2反应时，与金属结合的醌醇被氧化成对醌，其与金属中心的结合不那么强烈。因此，氧化使得多齿配体的配位性较低，从而增加了水合作用和r1。主要缺点是，大部分Mn（II）可能在氧化时释放，这既限制了r1响应，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，更紧密地结合的配体，功能羧酸盐，而不是吡啶进行了探索，这些预计结合的Mn（II）离子更紧密地比第一代配体，同时改善光谱响应。其次，将制备具有第一代和第二代配体的Ni（II）和Co（II）络合物，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，并且基于CEST的机制可以允许比T1加权成像对H2 O2更高的灵敏度。该项目还探讨了Mn（II）配合物以及它们的Ni（II），Co（II）和Zn（II）类似物的超氧化物歧化酶（SOD）活性。锌（II）配合物，到目前为止似乎是等效的抗氧化剂的锰（II）化合物，和拟议的工作将确定是否以及如何SOD活性可以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。

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.