Pt(IV) Anticancer Prodrugs - A Tale of Mice and Men

We would like to be able to design Pt(IV) prodrugs that can overcome resistance and minimize side effects. Unlike with the early exploration of Pt(II) anticancer agents where clear structure-activity relationships were defined, even after more than two decades of research on Pt(IV) prodrugs, there is no roadmap that can point us to the holy grail. Despite many excellent rational endeavors, we still have not found the "right" two axial ligands to append to the Pt(IV) derivatives of platinum(II) drugs that will "make platinum great again". So far this proved elusive, indicating that the design of Pt(IV) prodrugs is a difficult and frustrating task. Despite our better understanding of the biological processes and availability of advanced technologies, even our sophisticated rational plans often leave us disappointed and frustrated because at the end of the day, we are not able to outsmart the cancer cells or the mice, and just like Rosenberg, we might need to be rescued by serendipity.