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.
