Elusive intermediates in the breakdown reactivity patterns of prodrug platinum(IV) complexes

Kinetically inert platinum(IV) complexes are receiving growing attention as promising candidates in the effort to develop safe and valid alternatives to classical square-planar Pt(II) complexes currently used in antineoplastic therapy. Their antiproliferative activity requires intracellular Pt(IV)–Pt(II) reduction (activation by reduction). In the present work, a set of five Pt(IV) complexes has been assayed using mass spectrometry–based techniques, i.e., collision-induced dissociation (CID), and IR multiple photon dissociation (IRMPD) spectroscopy, together with ab initio theoretical investigations. Breakdown and reduction mechanisms are observed that lead to Pt(II) species. Evidence is found for typically transient Pt(III) intermediates along the dissociation paths of isolated, negatively charged (electron-rich) Pt(IV) prodrug complexes. [Figure not available: see fulltext.]