Photocytotoxic Pt(iv) complexes as prospective anticancer agents

Abstract

The use of Pt(IV) complexes as potential anticancer drugs is attractive, because they have higher stability and less side effects than Pt(II) compounds. Moreover, some Pt(IV) complexes can also be activated with light, opening an avenue to photochemotherapy. Our purpose is to widen the library of photoactivatable Pt(IV)-based prodrugs and here we report on the oxidation of the Pt(II) compound [PtCl(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (1) with PhICl₂ or H₂O₂. The synthetic procedure avoids the formation of multiple species: the treatment with PhICl₂ produces the Pt(IV) complex with axial chlorides, [PtCl₃(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (2), while H₂O₂ oxidation and post-synthesis carboxylation produce [Pt(OCOCH₃)₂Cl(4′-phenyl-2,2′:6′,2′′-terpyridine)][CF₃SO₃] (3), bearing acetates in the axial positions. 2 and 3 are stable in physiological-like buffers and in DMSO in the dark, but undergo photoreduction to 1 upon irradiation at 365 nm. Their stability toward reduction is a fundamental parameter to consider: cyclic voltammetry experiments show that the 2 electron reduction Pt(IV) → Pt(II) occurs at a more negative potential for 3, because of the greater stabilization provided by the acetate axial groups; noteworthily, 3 is stable for hours also in the presence of mM concentration of glutathione. The cytotoxicity of 2 and 3 toward A2780 and A2780cis cell lines reveals that 3 is the least toxic in the dark, but is able to produce cytotoxic effects far higher than cisplatin when irradiated. To shed light on the mechanistic aspects, the interaction with protein and DNA models has been explored through high-resolution mass spectrometry revealing that 2 and 3 behave as prodrugs, but are able to bind to biological targets only after irradiation.