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

在该项目中，由化学系化学结构、动力学和机理 B 项目资助，奥本大学化学与生物化学系的 Christian R. Goldsmith 教授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。这项研究的目标是开发用于磁共振成像（MRI）的氧化还原响应造影剂和超氧化物歧化酶的功能模拟物。鉴于活性氧与心血管、神经和炎症疾病有关，这些复合物可以为改善多种健康状况的诊断和治疗方案奠定基础。该项目处于无机化学、有机化学和生物化学的交叉领域。因此，它为本科生和研究生提供了良好的培训。该项目还赞助阿拉巴马州东部地区主要本科院校的研究研讨会，使学生能够参与尖端科学研究。最近发现，Mn(II) 与含对苯二酚的多齿配体的配合物表现出对 H2O2 的响应增强的 T1 加权弛豫率 (r1) 和催化降解超氧化物的能力。与 H2O2 反应后，与金属结合的醌醇被氧化成对醌，而对醌与金属中心的结合力较弱。因此，氧化降低了多齿配体的高度配位，从而增加了水合度和 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 反应，又对细胞造成危害。该项目试图以两种不同的方式解决稳定性问题。首先，探索以羧酸盐而不是吡啶为特征的更紧密结合的配体；预计这些配体将比第一代配体更紧密地与 Mn(II) 离子结合，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) 配合物，并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) 更强，并且基于 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) 复合物及其 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，Zn(II) 配合物似乎是与 Mn(II) 化合物等效的抗氧化剂，并且拟议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。

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.