Synthesis and DNA Interactions Study of Novel Fluorinated Pyridinium Platinum (IV) Complexes with Tumor Targeting Activity

Abstract Picoplatin can effectively circumvent cisplatin‐induced resistance through the “steric hindrance effect” of its structure, but there are still problems such as toxicity and side effects, so the search for safer, more efficient platinum analogs is crucial. Here we report three fluorinated pyridine‐containing Pt(IV) complexes employing biotin as an axial ligand to provide targeting functionality. Lipid solubility studies showed that all the synthesized complexes possessed improved lipid‐water partition coefficients, which are beneficial for transmembrane transport of drugs. The DNA binding activity of the compounds was studied using UV titration, fluorescence titration, and PicoGreen staining, demonstrating the presence of potential intercalation and electrostatic interaction binding modes. It probably attributable to planar π‐π interactions provided by the aromatic pyridine ligands. Meanwhile, molecular docking studies showed that the introduction of axial biotin molecules allowed the complexes to effectively target cancer cells, which was simultaneously confirmed by the results of cellular uptake studies. And another docking result showed that the Pt(IV) complexes binds to DNA by minor groove binding. The synthesized complexes exhibited similar cytotoxicity to cisplatin in five cell lines (SW480, HCT116, HepG2, A549 and LO2), with complex 3 being superior to the parent drug, picoplatin.