Triple-action Pt(IV) prodrugs of cisplatin and oxaliplatin with indole propionate and 4-phenylbutyrate ligands as potent anticancer agents.

The synthesis and biological activity of two new platinum(IV) derivatives of cisplatin and oxaliplatin with indole-3-propionate (IPA) and the histone deacetylase inhibitor 4-phenylbutyrate (PBA) in axial position are reported. Cis,cis,trans-[Pt(NH3)2Cl2(IPA)(PBA)] (1) and trans-[Pt(DACH)(OX)(IPA)(PBA)] (2) (DACH = (1R,2R)-1,2-cyclohexanediamine; OX = oxalate) were characterized by elemental analysis, ESI-MS, FT-IR, and 1H, 13C{1H}, and 195Pt{1H} NMR spectroscopy. The cytotoxicity of the Pt(IV) complexes was evaluated in A2780 ovarian, A549 lung, PEA1 ovarian, SKOV3 ovarian, PC3 prostate and HCT116 colon cancer cells. Complex 2 is about 100 times more potent than cisplatin and about 30 times more potent than oxaliplatin in HCT116 cells. In contrast to cisplatin and oxaliplatin, 1 and 2 maintain their activity in HCT116 p53-knockout cells. Mechanistic studies indicated a multifactorial mechanism that includes histone deacetylase inhibition, the generation of reactive oxygen species and the disruption of mitochondrial function. The complexes affect the cell cycle and induce apoptotic cell death.