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

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 ¹H and ¹⁹⁵Pt 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.