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

Authors

• Magy A. Mekhail, Chapman UniversityFollow
• David M. Freire, Texas Christian University
• Cameron Bowers, Texas Christian University
• Grant Elam, Texas Christian University
• Nora Del Bosque, Texas Christian University
• Hannah K. Pyle, Texas Christian University
• Sarah K. Dunn, Texas Christian University
• Spencer Lanyon, Texas Christian University
• Timothy J. Hubin, Southwestern Oklahoma State University
• Giridhar Akkaraju, Texas Christian University
• Kayla N. Green, Texas Christian University

Document Type

Article

Publication Date

6-16-2026

Abstract

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.

Comments

This article was originally published in Inorganic Chemistry, volume 65, issue 25, in 2026. https://doi.org/10.1021/acs.inorgchem.6c01041

Recommended Citation

Mekhail, M. A.; Freire, D. M.; Bowers, C.; Elam, G.; Del Bosque, N.; Pyle, H. K.; Dunn, S. K.; Lanyon, S.; Hubin, T. J.; Akkaraju, G.; Green, K. N. Antioxidant potential of a non-heme iron complex: Mitigating H₂O₂-induced cellular damage. Inorg. Chem. 2026, 65, 25, 13922–13931. https://doi.org/10.1021/acs.inorgchem.6c01041

Copyright

The authors

Creative Commons License

This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 4.0 License.