A view on multi-action Pt(IV) antitumor prodrugs

Platinum(IV) complexes are particularly appealing as prodrugs since their relative inertness, and consequent low toxicity outside the cell is matched by their high activity inside the tumor cells upon reduction to their corresponding Pt(II) counterparts. Synthetic routes to such systems, with particular emphasis on the bioactivity of the removable axial ligands, are described herein. The kinetics and mechanisms of these reductive elimination processes are still not completely unraveled, and many questions remain unresolved. We here present some of the more relevant examples of multi-action Pt(IV) complexes often grouped around their prototypal prodrugs (i.e., mitaplatin and mitochondria-targeted complexes, ethacraplatin and glutathione S-transferase-targeted complexes, asplatin or platin-A and inhibitors of cyclooxygenases). In addition, Pt(IV) conjugates with histone deacetylase inhibitors (HDACi) and "true" multiple-action complexes are exhaustively discussed. These Pt(IV) conjugates contain adjuvant agents able to inhibit some specific (typically enzymatic) mechanism characteristic of, or more active in, tumor cells. These agents are able to act synergistically or at least additively with cisplatin and its congeners and overcome intrinsic or acquired chemoresistance. Finally, we emphasize the need for a multidisciplinary approach in the battle against cancer using metallo-drugs by involving not only inorganic chemists, but also biochemists, molecular biologists and, of course, clinicians.