Ligand substitution reactions afford oxaliplatin-based platinum (IV) complexes bearing axial alkoxido ligands

The application of new synthetic methods in the area of platinum(IV) anticancer prodrugs greatly increases the availability of accessible chemical entities that can be conjugated to the platinum(IV) center. These new axial ligands not only endow platinum(IV) complexes with unique properties but also inspire new concepts in platinum(IV)-based prodrug design and development. Herein, oxaliplatin-based platinum(IV) complexes are synthesized with axial alkoxido ligands via a ligand substitution reaction. In the presence of base, alcohol molecules can spontaneously replace the labile axial trifluoroacetato ligand and transform into new alkoxido ligands in platinum(IV) complexes. Further investigations indicate that compared with carboxylato ligands, the axial alkoxido ligands more greatly improve the hydrolytic and reductive stability of platinum(IV) complexes. Cytotoxicity studies suggest that alkoxido platinum(IV) complexes exert less activity against cancer cells than that of their carboxylated platinum(IV) analogues under similar cellular platinum accumulation levels, which could be attributed to their improved stability. This research provides a new strategy to synthesize alkoxido platinum(IV) complexes, which are expected to have significant applications as platinum(IV)-based anticancer prodrugs. © 2023 The Royal Society of Chemistry.