Rings of Power: Controlling SOD Mimic Activity by the Addition of Pyridine Rings within the Pyridinophane Scaffold

Superoxide dismutase enzymes are a major defense against superoxide, which is a potent reactive oxygen species. Misregulation of reactive oxygen species and subsequent neuronal damage are etiological hallmarks of neurodegenerative disease. Macrocyclic small molecules have offered inroads toward functional SOD1 mimics. Herein, we report a series of five tetra-aza macrocyclic ^<b>R</b><b>Py</b>_<b>2</b><b>N</b>_<b>2</b> ligands, varied by 4-position substitution of the pyridine ring with both electron-donating (R = OMe) and withdrawing groups (R = Cl, I, and CF₃) to offer the first comparison to well-studied ^<b>R</b><b>PyN</b>_<b>3</b> congeners and other mimics in the literature. New ligands have been characterized by NMR, mass spectrometry, elemental analysis, and potentiometric titrations (p<i>K</i>_a). Cyclic voltammetry and X-ray diffraction analysis of the copper(II) complexes (<b>Cu</b>^<b>II</b><b>(</b>^<b>R</b><b>Py</b>_<b>2</b><b>N</b>_<b>2</b><b>)</b>^<b>2+</b>) demonstrate how pyridine substitution impacts the metal center. This data, and evaluation of the log β_Cu(II) and log β_Cu(I) within the series, indicates significant improvement to the binding affinity for Cu(I) without sacrifice of Cu(II) binding. The <b>Cu</b>^<b>II</b><b>(</b>^<b>R</b><b>Py</b>_<b>2</b><b>N</b>_<b>2</b><b>)</b>^<b>2+</b> series yield the highest <i>k</i>_cat for any Cu(II)-based small molecule functional SOD1 mimic (<i>k</i>_cat = 45.36 M^-1 s^-1). Furthermore, the <b>Cu</b>^<b>II</b><b>(</b>^<b>OMe</b><b>Py</b>_<b>2</b><b>N</b>_<b>2</b><b>)</b>^<b>2+</b> and <b>Cu</b>^<b>II</b><b>(</b>^<b>CF₃</b><b>Py</b>_<b>2</b><b>N</b>_<b>2</b><b>)</b>^<b>2+</b> complexes were studied in FRDA cells to determine cell toxicity as a first step toward the application of these mimics as therapeutics for neurological disease.