Hydrogen peroxide ‐ responsive aminoferrocene prodrugs

Aminoferrocene (AF)‐based prodrugs are activated in cancer cells through reactions with H₂O₂ and other reactive oxygen species (ROS), generating electron‐rich AF’s. These, in turn, induce the production of highly toxic O2·‐ and HO·, leading to cancer cell death. Effective activation of these prodrugs depends on their ability to target intracellular organelles rich in ROS, as non‐targeted prodrugs are practically inactive. In this study, we replaced the boronic acid pinacol ester—previously used as a ROS‐trigger—with an α‐ketoamide fragment, which is more selective and sensitive to H₂O₂. This modification enhanced the anticancer efficacy of untargeted AF prodrugs, reducing the IC₅₀ from 23.9–35.5 μM (previously reported prodrug 13b) to 5–6.4 μM (new prodrug 2a) in human ovarian cancer A2780 and Burkitt’s lymphoma BL‐2 cells. Further analysis confirmed that the anticancer effect of 2a is driven by its ability to markedly increase intracellular ROS levels in both the cytoplasm and mitochondria.