Antioxidant Potential of a Non-Heme Iron Complex: Mitigating H ₂ O ₂ -Induced Cellular Damage

High Resolution Image Download MS PowerPoint Slide 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 H 2 O 2 mitigation in aqueous environments. Here, we investigate water-soluble nonheme iron complexes derived from 12-membered pyridinophanes ( CF 3 PyN 3, PyN 3, NMe 2 PyN 3, and Py 2 N 2 ) to evaluate the impact of ligand scaffolds on H 2 O 2 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 H 2 O 2 disproportionation activity. Electron-donating substituents accelerate turnover but reduce stability, while electron-withdrawing groups enhance robustness at the expense of rate. The unsubstituted Fe(PyN 3 ) 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(Py 2 N 2 ) 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(PyN 3 ) 3+ was shown to mitigate H 2 O 2 -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.