Halogenated Pt^IV Complexes from N-Halosuccinimide Oxidation of Pt^II Antitumor Drugs: Synthesis, Mechanistic Investigation, and Cytotoxicity

Compared with square-planar Pt^II drugs, Pt^IV-based anticancer prodrugs are relatively inert under physiological conditions and can be activated after entering cells. The two axial ligands in Pt^IV complexes provide an opportunity to further functionalize these prodrugs. In recent years, much effort has been devoted to developing new Pt^IV-based anticancer prodrugs with higher cytotoxicity but fewer side effects. New synthetic methods, however, are intensely desired for structurally diversified and biologically distinct Pt^IV complexes. Herein, we utilize N-halosuccinimides as oxidants and carry out the oxidation reaction on Pt^II drugs including cisplatin, carboplatin, and oxaliplatin to obtain halogenated Pt^IV complexes. The related mechanism of the reaction of N-bromosuccinimide (NBS) with cisplatin in ethanol is thoroughly investigated. N-chlorosuccinimide is also utilized to obtain the respective dichlorinated Pt^IV complexes. When N-iodosuccinimide reacts with Pt^II drugs, new Pt^IV compounds containing iodide and succinimide ligands in the axial position are formed. Cytotoxicity test shows that some of the complexes are active against cisplatin-resistant human ovarian cancer cells. Our study provides a detailed understanding of the reaction mechanism between NBS and cisplatin and offers a more convenient strategy to obtain dichlorinated and new iodinated Pt^IV anticancer prodrugs.