An overview of recent advancements in anticancer Pt(IV) prodrugs: New smart drug combinations, activation and delivery strategies

The discovery of the antineoplastic properties of cisplatin in 1965 by Rosenberg and co-workers, originated a renewed attraction for metal complexes for medicinal applications. Indeed, after its first outstanding clinical results, chemists involved in the metal complexes research field readily started to study safer and more effective alternatives to cisplatin itself. In this frame, after decades of intensive research mainly focused on classical Pt(II) compounds, also platinum(IV)-based compounds have been taken into account. The reason for this interest is that, despite the kinetic inertness of Pt(IV) compounds, they can undergo to “in-cell” reduction process which is able to activate the platinum centre through the generation of the more reactive Pt(II) counterpart. This kind of approach might offer some relevant advantages, such as the reduction of severe side effects associated with Pt(II) off-target reactions. Indeed, the lower redox potential of cancer cells with respect to the healthy ones is able to trigger the Pt(IV) reduction into the biologically active counterpart. In this review, we summarized the most recent goals achieved in the field of so-called Pt(IV) prodrugs.