Rings of Power:\nControlling SOD Mimic Activity by\nthe Addition of Pyridine Rings within the Pyridinophane Scaffold

Superoxide dismutase enzymes are a major defense against\nsuperoxide,\nwhich is a potent reactive oxygen species. Misregulation of reactive\noxygen species and subsequent neuronal damage are etiological hallmarks\nof neurodegenerative disease. Macrocyclic small molecules have offered\ninroads toward functional SOD1 mimics. Herein, we report a series\nof five tetra-aza macrocyclic <sup><b>R</b></sup><b>Py</b><sub><b>2</b></sub><b>N</b><sub><b>2</b></sub> ligands,\nvaried by 4-position substitution of the pyridine ring with both electron-donating\n(R = OMe) and withdrawing groups (R = Cl, I, and CF<sub>3</sub>) to\noffer the first comparison to well-studied <sup><b>R</b></sup><b>PyN</b><sub><b>3</b></sub> congeners and other mimics\nin the literature. New ligands have been characterized by NMR, mass\nspectrometry, elemental analysis, and potentiometric titrations (p<i>K</i><sub>a</sub>). Cyclic voltammetry and X-ray diffraction\nanalysis of the copper(II) complexes (<b>Cu</b><sup><b>II</b></sup><b>(</b><sup><b>R</b></sup><b>Py</b><sub><b>2</b></sub><b>N</b><sub><b>2</b></sub><b>)</b><sup><b>2+</b></sup>) demonstrate how pyridine substitution\nimpacts the metal center. This data, and evaluation of the log β<sub>Cu(II)</sub> and log β<sub>Cu(I)</sub> within the series, indicates\nsignificant improvement to the binding affinity for Cu(I) without\nsacrifice of Cu(II) binding. The <b>Cu</b><sup><b>II</b></sup><b>(</b><sup><b>R</b></sup><b>Py</b><sub><b>2</b></sub><b>N</b><sub><b>2</b></sub><b>)</b><sup><b>2+</b></sup> series yield the highest <i>k</i><sub>cat</sub> for any Cu(II)-based small molecule functional\nSOD1 mimic (<i>k</i><sub>cat</sub> = 45.36 M<sup>–1</sup> s<sup>–1</sup>). Furthermore, the <b>Cu</b><sup><b>II</b></sup><b>(</b><sup><b>OMe</b></sup><b>Py</b><sub><b>2</b></sub><b>N</b><sub><b>2</b></sub><b>)</b><sup><b>2+</b></sup> and <b>Cu</b><sup><b>II</b></sup><b>(</b><sup><b>CF<sub>3</sub></b></sup><b>Py</b><sub><b>2</b></sub><b>N</b><sub><b>2</b></sub><b>)</b><sup><b>2+</b></sup> complexes\nwere studied in FRDA cells to determine cell toxicity as a first step\ntoward the application of these mimics as therapeutics for neurological\ndisease.