Cytotoxicity and ROS production of novel Pt(IV) oxaliplatin derivatives with indole propionic acid

Abstract

The coordination of biologically active moieties to the axial positions of Pt(IV) derivatives of Pt(II) anticancer drugs allows the co-delivery and simultaneous activation of two pro-drugs for combination therapy. Pt(IV) complexes with a redox modulator as an axial ligand can kill cancer cells by a mechanism combining DNA platination and generation of oxidative stress. In this study we evaluated the cytotoxicity of Pt(IV) complexes based on the oxaliplatin scaffold and the pro-oxidant indole-3-propionate in cisplatin-sensitive and cisplatin-resistant ovarian cancer cells. A series of five complexes was synthesized and characterized by H-1 and Pt-195 NMR spectroscopy, IR spectroscopy, mass spectrometry and elemental analysis; trans-[Pt(DACH)(ox)(IPA)(OH)] (1), trans-[Pt(DACH)(ox)(IPA)(2)] (2), trans-[Pt(DACH)(ox)(IPA)(bz)] (3), trans-[Pt(DACH)(ox)(IPA)(suc)] (4), and trans-[Pt(DACH)(ox)(IPA)(ac)] (5) (DACH = 1,2-diaminocyclohexane (1R, 2R)-(-), ox = oxalate, IPA = indole 3-propionate, bz = benzoate, suc = succinate and ac = acetate). The complexes were shown to produce cellular reactive oxygen species (ROS) in a time-dependent manner. The most potent ROS producer, complex 1, also elicited the highest cytotoxicity. Complex 1 was shown to form the mono-and bis-adducts [Pt(DACH)(guanosine)( OH)](+) and [Pt(DACH)(guanosine)(2)](2+) in the presence of ascorbic acid, suggesting that on activation the released oxaliplatin will interact with DNA.