Oxidative Stress Induced by Pt(IV) Pro-drugs Based on the Cisplatin Scaffold and Indole Carboxylic Acids in Axial Position

Abstract

The use of Pt(IV) complexes as pro-drugs that are activated by intracellular reduction is a widely investigated approach to overcome the limitations of Pt(II) anticancer agents. A series of ten mono- and bis-carboxylated Pt(IV) complexes with axial indole-3-acetic acid (IAA) and indole-3-propionic acid (IPA) ligands were synthesized and characterized by elemental analysis, ESI-MS, FT-IR, 1H and 195Pt NMR spectroscopy. Cellular uptake, DNA platination and cytotoxicity against a panel of human tumor cell lines were evaluated. All the complexes are able to overcome cisplatin-resistance and the most potent complex, cis,cis,trans-[Pt(NH3)2Cl2(IPA)(OH)] was on average three times more active than cisplatin. Mechanistic studies revealed that the trend in cytotoxicity of the Pt(IV) complexes is primarily consistent with their ability to accumulate into cancer cells and to increase intracellular basal reactive oxygen species levels, which in turn results in the loss of mitochondrial membrane potential and apoptosis induction. The role of the indole acid ligand as a redox modulator is discussed.

Antitumor platinum(IV) derivatives of carboplatin and the histone deacetylase inhibitor 4-phenylbutyric acid

“…The 195 Pt NMR spectra of the bis-substituted complexes ( Supplementary Figs. S6 -S10) showed a quintet around 1900 ppm while 1 gave a quintet at 1741 ppm in line with chemical shift data previously reported for related Pt(IV) complexes [14]. The appearance of the signals as quintets is due to spin-to-spin coupling between 195 Pt and two 14 N nuclei.…”

“…S6 -S10) showed a quintet around 1900 ppm while 1 gave a quintet at 1741 ppm in line with chemical shift data previously reported for related Pt(IV) complexes [14]. The appearance of the signals as quintets is due to spin-to-spin coupling between 195 Pt and two 14 N nuclei. The mass spectra of the complexes displayed a peak in the negative mode with the typical platinum isotope pattern corresponding to the respective [M − H] − species ( Supplementary Figs.…”

“…Interestingly, there is no correlation between lipophilicity and cellular internalization. Although this is somewhat unexpected, since, unlike Pt(II) complexes, Pt(IV) complexes are believed to enter cells solely by passive diffusion, a similar lack of correlation between logP values and cellular Pt accumulation has been reported for other Pt(IV) systems [14,38,58,59].…”

“…1). Furthermore, phosphatase 2A inhibitors [8], the vitamin E analog α-tocopheryl succinate [9], carbohydrates [10,11], nucleotide excision repair inhibitors [12], alkylating agents [13] as well as redox modulators [14] have been attached to the cisplatin and oxaliplatin scaffold.…”

Three Reactions, One Catalyst: A Multi‐Purpose Platinum(IV) Complex and its Silica‐Supported Homologue for Environmentally Friendly Processes

“…The Pt(IV) complexes are considered pro‐drugs in cancer therapy, due to their ability to be reduced in the biological medium forming Pt(II) complexes which are the active species able to bind DNA . Pt(IV) was also found active against cancer cells in certain complexes, being able to overcome cisplatin resistance, and suitable for targeted chemotherapy . Generally, Pt(IV) complexes are considered to have higher kinetic inertness due to their octahedral geometry and low‐spin d 6 electronic configuration and reduced side reactions with biomolecules, although exceptions were noticed .…”