Unique Use of Alkylation for Chemo-Redox Activity by a Pt^IV Prodrug

Resistance towards chemotherapeutics displayed by cancer cells is a significant stumbling block against fruitful cisplatin-based therapy. A unique dual-acting chemotherapeutic modality, Platin-B, a prodrug of cisplatin and pipobroman-mimicking alkylating agent, was constructed to circumvent tumor resistance. Platin-B exhibited a superior cytotoxicity profile in cisplatin-resistant cancer cells. Enhanced activity and the ability to overcome cancer-induced resistance of Platin-B was related to adduct formation with intracellular glutathione, followed by the activity of Platin-B on the mitochondria of cells, along with its conventional nuclear activity. Alkylating moieties present on Platin-B enhanced its cellular and subcellular concentration and protected it from early drug sequestration by biological thiols. A unique dual-acting chemotherapeutic modality Platin-B, a prodrug of Pt^IV and pipobroman-mimicking alkylating agent, was constructed to act on the mitochondria of cells by using its pendent -Br moieties to induce changes in mitochondrial bioenergetics, formation of repair-inactive Pt-DNA adducts, and ultimately participation in mitochondrial apoptosis and loss of mitochondrial mass to overcome resistance compared to other similar Pt-based compounds.