Arene Ru(II) Complexes with Difluorinated Ligands Act as Potential Inducers of S-Phase Arrest via the Stabilization of G-Quadruplex DNA.

Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(-arene)(L)Cl] ( = 2-(2,3-difluorophenyl)imidazole[4,5][1,10]-phenanthroline; = 2-(2,4-difluorophenyl)imidazole[4,5][1,10]-phenanthroline; arene = benzene, toluene, and -cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to G-quadruplex DNA through either groove binding or - stacking, and the relative difluorinated site in the main ligand plays a role in regulating the binding mode. The binding behavior of these complexes with G-quadruplex DNA was evaluated using ultraviolet-visible spectroscopy, fluorescence intercalator displacement assay, fluorescence resonance energy transfer melting assay, and polymerase chain reaction. The comprehensive analysis indicated that complex exhibited a better affinity and stability in relation to G-quadruplex DNA with a DC of 6.6 μM and Δ values of 13.09 °C, than other molecules. Further activity evaluation results displayed that this class of complexes can also inhibit the growth of various tumor cells, especially complexes and , which exhibited a better inhibitory effect against human U87 glioblastoma cells (51.61 and 23.75 μM) than other complexes, even superior to cisplatin (32.59 μM). Owing to a befitting lipophilicity associated with the high intake of drugs by tumor cells, complexes and had favorable lipid-water partition coefficients of -0.6615 and -0.8077, respectively. Moreover, it was found that complex suppressed the proliferation of U87 cells mainly through an induced obvious S phase arrest and slight apoptosis, which may have resulted from the stabilization of G-quadruplex DNA to block the transcription and expression of . In brief, these types of arene Ru(II) complexes with difluorinated ligands can be developed as potential inducers of S-phase arrest and apoptosis through the binding and stabilization of G-quadruplex DNA, and could be used in clinical applications in the future.