Boron-based prodrug demonstrates tumor growth reduction in triple-negative breast cancer, suggesting reactive oxygen species activation pathway.
Boron-based reactive oxygen species (ROS)-activated prodrugs offer a promising strategy for enhancing cancer selectivity, yet their in vivo activation remains poorly defined. We report a novel H₂O₂-responsive phenylboronic nitrogen mustard prodrug (10a) and its precisely deuterated analogue (10b), designed to elucidate the activation pathway of ROS-responsive agents. These isotopologues differ only in ethyl substituents─hydrogen (10a) versus deuterium (10b)─enabling isotope-resolved tracking of metabolic transformations in vivo. Co-administration of 10a and 10b in triple-negative breast cancer xenograft mice identified two metabolites, providing the first definitive in vivo evidence of oxidative deboronation as the primary activation mechanism. Prodrug 10a exhibited H₂O₂-inducible DNA-alkylating activity, selectively inhibited the proliferation of high ROS-expressing MDA-MB-468 cancer cells over nonmalignant MCF-10A cells, markedly suppressed tumor growth without observable toxicity. This study highlights precision deuteration as a mechanistic probe and establishes a platform for rational design and optimization of boron-based anticancer prodrugs.
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Saxon et al. (2025) studied this question.
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