Metal‐Center‐Controlled Fenton‐Like Reactivity of Biomimetic First‐Row Transition Metal Complexes in Aqueous Anticancer Catalysis

ABSTRACT Catalytic oxidative cancer therapy exploits elevated hydrogen peroxide levels within tumor microenvironments to induce selective oxidative damage in malignant cells. However, many ROS‐generating therapeutic systems rely on heavy metals or structurally complex inorganic architectures, limiting their biological compatibility and catalytic selectivity. Inspired by nonheme iron‐mediated redox catalysis, we report a series of water‐soluble biomimetic first‐row transition metal complexes supported by a picolylamine‐derived nonheme ligand scaffold bearing a pendant hydroxyl group. Systematic variation of the metal center (Mn, Fe, Co, Ni, Cu, and Zn) generated divergent electrochemical behavior and distinct peroxide‐activation reactivity, yet only the iron complex, [Fe(N 2 Py 3 OH)] 2+ ( 1‐Fe ), promoted hydroxyl radical formation via Fenton‐like hydrogen peroxide activation in water. Spectroscopic, electrochemical, and crystallographic analyses revealed a biomimetic coordination environment that stabilizes a quasi‐reversible Fe(II)/Fe(III) redox couple suited to catalytic peroxide activation. In gastric cancer cells, 1‐Fe induced intracellular oxidative stress, mitochondrial depolarization, lipid peroxidation, and concomitant apoptosis and ferroptosis, while exhibiting negligible toxicity toward normal fibroblasts. In combination with paclitaxel, 1‐Fe produced synergistic antiproliferative activity in vitro and suppressed peritoneal tumor dissemination in vivo without overt systemic toxicity. Collectively, these results establish biomimetic iron complexes as molecular platforms for Fenton‐like oxidative catalysis in redox‐based cancer therapy.