Anticancer activity of multifunctional Pt(IV) prodrugs

The anticancer activity of Pt(II)-based drugs is limited by severe side effects, resistance and poor pharmacokinetic profile. To overcome these limits Pt(IV) prodrugs can be used: they are activated by reduction within hypoxic tumor environment, releasing the corresponding Pt(II) complex and two axial ligands, which can also be bioactive molecules, providing a synergistic activity with Pt(II) drugs (multi-action agents). The biological properties of such molecules have been reported in this thesis. A cisplatin-based Pt(IV) complex containing the Histone DeAcetylase inhibitor (HDACi) 2-(2-propynyl)octanoate (POA) as axial ligand showed a marked in vitro and in vivo anticancer activity compared with cisplatin and a Pt(IV) compound with two other known HDACis. Also a Pt(IV) derivate bearing POA but based on the oxaliplatin-analogue cis-dichlorido(cyclohexane-1R,2Rdiamine) platinum(II) (or [PtCl2(dach)]) was 1-2 orders of magnitude more active in vitro than the references cisplatin, oxaliplatin and [PtCl2(dach)], due to its high cellular accumulation. It exerted also a marked in vivo anticancer activity, inducing immunogenic cell death on colon cancer. The selectivity towards colon cancer of dach-based complexes was confirmed by the investigation of three couples of asymmetric Pt(IV) species, cisplatin- or dach-based, containing the bioactive axial ligands clofibrate, heptanoate or octanoate. The two series showed a marked in vitro antiproliferative activity (on 2D and 3D models) compared to the Pt(II) counterparts, due to a considerable accumulation in cancer cells. Finally, two cisplatin-based Pt(IV) complexes, containing inhibitors of cyclooxygenase (COX) enzymes as axial ligands, offered good antiproliferative performances, due to their enhanced lipophilicity. However, their biological effects were almost independent from COX-2 expression. In conclusion, the use of bioactive ligands leads to multi-action Pt(IV) complexes with promising pharmacological profile.