Recent advances in the synthesis, stability, and activation of platinum(IV) anticancer prodrugs

Platinum-based anticancer drugs have been widely applied in clinical settings for more than 40 years. The remarkable breakthroughs that have come from the use of these complexes in cancer therapy have stimulated a continual search for new platinum anticancer drugs. The most promising result of these efforts is a prodrug strategy based on the use of platinum(IV) versions of the traditional platinum(II) anticancer drugs. Hence, the design of synthetic methods for platinum(IV) prodrugs and an understanding of their hydrolytic stability and intracellular activation processes are critical for the development of platinum(IV) prodrugs for cancer therapy. In this review, we summarize recent progress in this field from a comprehensive viewpoint, with an emphasis first on the oxidation processes in chemical environments where platinum(II) compounds are converted to their platinum(IV) species, followed by the reduction processes in biological environments where platinum(IV) species are converted back to platinum(II) forms. First, recent approaches that use new oxidizing reagents to synthesize platinum(IV) prodrugs are summarized, and the oxidation mechanisms and outer-sphere functionalization of platinum(IV) prodrugs are examined. Second, the hydrolysis of platinum(IV) complexes, which has sometimes been underexplored, is discussed, and the factors associated with the hydrolytic stability of platinum(IV) complexes are reviewed. Last, we focus on the reduction of platinum(IV) prodrugs, from the perspectives of reduction potential, rate of reduction, reducing agents, and reduction products. The need for new strategies to achieve controllable intracellular reduction of platinum(IV) prodrugs is emphasized. This review aims to help researchers to improve their understanding of platinum(IV) anticancer prodrugs and hopefully to generate new ideas, strategies, and applications in the area of metal-based drugs.