Antioxidant Potential of a Non-Heme Iron Complex: Mitigating H₂O₂-Induced Cellular Damage

Iron complexes with antioxidant activity have garnered significant interest for both general and medical applications, yet few studies have yielded functional nonheme iron-based mimics for H₂O₂ mitigation in aqueous environments. Here, we investigate water-soluble nonheme iron complexes derived from 12-membered pyridinophanes (^CF₃PyN₃, PyN₃, ^NMe₂PyN₃, and Py₂N₂) to evaluate the impact of ligand scaffolds on H₂O₂ decomposition activity both in vitro and in a cellular model. Speciation and kinetic analyses reveal that both electronic and geometric modulation of the macrocyclic ligand framework govern H₂O₂ disproportionation activity. Electron-donating substituents accelerate turnover but reduce stability, while electron-withdrawing groups enhance robustness at the expense of rate. The unsubstituted Fe(PyN₃)³⁺ complex achieves the optimal balance, exhibiting the highest catalytic efficiency (k = 1.45 M^-1 s^-1) and turnover number (TON = 33) under physiological conditions. Crystallographic characterization of the Fe(Py₂N₂)³⁺ complex, reported here for the first time, revealed a μ-oxo-bridged dimeric structure that rationalizes its diminished reactivity. Collectively, these findings define key design parameters for constructing stable, Fenton-resistant nonheme iron catalysts. Extending this chemistry to a biological context, Fe(PyN₃)³⁺ was shown to mitigate H₂O₂-induced oxidative stress in HeLa cells by catalytically reducing intracellular ROS levels and improving cell viability. The integration of molecular, mechanistic, and cellular data demonstrates that well-defined iron-pyridinophane frameworks can translate homogeneous catalytic behavior into complex biological systems, offering a foundation for the design of therapeutic antioxidant catalysts.