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

在该项目中，奥本大学化学和生物化学系的克里斯蒂安·R·戈德史密斯教授在化学系化学结构、动态和机理B计划的资助下，正在开发能够检测和/或降解活性氧的新的过渡金属络合物。这项研究的目标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响应性造影剂。鉴于活性氧参与心血管、神经和炎症性疾病，这些复合体可以形成基础，以改进诊断和治疗方案，为广泛的健康状况。该项目处于无机化学、有机化学和生物化学的交界处。因此，它为本科生和研究生提供了极好的培训。该项目还在东阿拉巴马州地区的主要本科生机构举办研究研讨会，使他们的学生能够参与尖端科学研究。最近发现，含对苯二酚的多齿配体的锰(II)配合物对H_2O_2具有增强的T1加权弛豫度(R_1)和催化降解超氧化物的能力。当与双氧水反应时，金属结合的对苯二酚被氧化成对苯二酚，对苯二酚与金属中心的结合不那么强烈。因此，氧化使多齿配体的高度配位性降低，从而增加了水合作用和R1。主要的缺点是，许多Mn(II)很可能在氧化时释放，这既限制了R1的响应，又对细胞构成了危险。该项目试图通过两种不同的方式来解决稳定性问题。首先，探索了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，第一代和第二代配体的Ni(II)和Co(II)络合物将作为化学交换饱和转移(CEST)衍生的磁共振造影剂进行制备和评估。Ni(II)和Co(II)与配体的结合比与Mn(II)的结合更强，基于CEST的机制可以比T1加权成像对H_2O_2更敏感。该项目还研究了锰(II)络合物及其镍(II)、钴(II)和锌(II)类似物的超氧化物歧化酶(SOD)活性。到目前为止，锌(II)配合物似乎与锰(II)化合物具有同等的抗氧化剂，拟议的工作将确定是否以及如何使用具有氧化还原活性的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.