This Is AuburnElectronic Theses and Dissertations

Coordination Complexes with Redox-Active Macrocyclic Ligands as Redox-Responsive 1H and 19F MRI Contrast Agent Sensors and Catalysts for the Degradation of Hydrogen Peroxide




Karbalaei, Sana Jr

Type of Degree

PhD Dissertation


Chemistry and Biochemistry


Abstract Reactive oxygen species (ROS), including hydroxyl radicals (·OH), superoxide anions (O2-), and hydrogen peroxide (H2O2), play vital roles in cell signaling and cellular signal transduction; however, the overproduction of ROS has been associated with inflammatory, cardiovascular, and neurological diseases. To better understand the connections between ROS and diseases, we need to develop non-invasive and reliable sensors that can monitor the overproduction and traffic of ROS within biological systems. Magnetic resonance imaging (MRI) is particularly useful for non-invasive whole-body imaging due to its superior visualization depth, and MRI contrast agents are commonly used to change the T1-weighted relaxivity (r1) of protons and improve image contrast. To this end, I have reported a series of macrocyclic redox-responsive manganese- and iron-based MRI contrast agents that respond to H2O2, the most abundant ROS in biology. Upon reaction with H2O2, metal oxidation results in an increase in the relaxivity of the iron-containing sensor; with the manganese complex, conversely, the enhanced relaxivity results from the oxidation of the organic ligand. Furthermore, it has been demonstrated that the inclusion of the macrocycle into the ligand structure improves the thermodynamic and kinetic stabilities of the MRI contrast agent sensors while amplifying the response to H2O2. To resolve the problem of false positives for 1H MR imaging due to the background signal of water molecules, a fluorinated quinol-containing compound and its Fe(II) complex were developed as a dual-mode MRI contrast agent. Before oxidation, the sensor has a strong 19F MRI signal but does not provide adequate T1-weighted 1H MRI contrast. Upon reaction with H2O2, the 19F MRI signal disappears as the r1 for 1H MRI intensifies. High concentrations of ROS can overwhelm the body's defenses against oxidative stress; these defenses include superoxide dismutases (SODs), which catalyze the conversion of O2·- to O2 and H2O2, and catalases (CATs), which promote the dismutation of H2O2 to O2 and H2O. The development of small molecules capable of replicating this catalysis represents a therapeutic strategy to combat disorders affiliated with oxidative stress. In this dissertation, I synthesized a series of quinol-containing compounds consisting of redox-active and redox-inactive metal ions to act as potent antioxidants that mimic either SOD and/or CAT. Further investigation revealed that the mechanistic pathway of hydrogen peroxide degradation can proceed using either metal- or ligand-centered redox partners for the ROS.