Pt(IV) prodrugs containing aliphatic amine in axial ligands with anticancer properties: Advanced synthesis, solubility, reduction, cytotoxicity, cell mechanism, DNA interaction, molecular docking, and molecular dynamics simulations.

To reduce side effects and drug resistance associated with clinical Pt(II) drugs used in cancer treatment, Pt(IV) derivatives have been developed because of their improved stability and solubility. In this study, we designed, synthesized, and characterized novel Pt(IV) prodrugs based on carboplatin, bearing both symmetric and unsymmetric axial ligands, including octylamine. The stability and reduction behavior of these Pt(IV) compounds were studied in phosphate-buffered saline, with and without the presence of reducing agents such as ascorbic acid. We also evaluated their solubility and lipophilicity in comparison to clinical platinum drugs. DFT data along with geometry parameters were obtained, and the reduction mechanism was investigated through theoretical studies. The biological properties of these compounds were also evaluated against human breast cancer (MCF-7) and noncancerous (MCF-10 A) cell lines. Our results show that the Pt(IV) prodrugs are more cytotoxic and exhibit higher intracellular accumulation than carboplatin, which may be attributed to lower hydrolysis rates and slower reduction to their corresponding intermediates. The apoptotic mechanism of cell death was evaluated by flow cytometry. The DNA binding affinities of all Pt(IV) complexes were determined using UV-Vis and CD spectroscopy, as well as computational molecular docking and molecular dynamics simulations. Molecular dynamics simulations, based on RMSF and helical bending angle analyses, revealed that DNA becomes destabilized in the presence of the complexes. This study provides valuable insights into the selection of appropriate axial ligands for the rational design of new Pt(IV) prodrugs derived from clinical Pt drugs for cancer treatment.