Hydrogen Peroxide‐Responsive Aminoferrocene Prodrugs

To improve sensitivity toward H₂O₂, the boronic acid pinacol ester in known aminoferrocene-based anticancer prodrug 13b is replaced with an α-ketamide fragment to obtain prodrug 2a and some of its N-alkylated derivatives. 2a exhibits substantially improved cytotoxicity in vitro toward ovarian cancer A2780 and Burkitt's lymphoma BL-2 cells. Its mode of action relies on intracellular generation of reactive oxygen species.

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 nontargeted prodrugs are practically inactive. In this study, the boronic acid pinacol ester—previously used as a ROS-trigger—is replaced with an α-ketoamide fragment, which is more selective and sensitive to H₂O₂. This modification enhances 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 confirms that the anticancer effect of 2a is driven by its ability to markedly increase intracellular ROS levels in both the cytoplasm and mitochondria.

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