| Summary: | Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(<i>η</i><sup>6</sup>-arene)(L)Cl] (<b>L</b><b><sub>1</sub></b> = 2-(2,3-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; <b>L</b><b><sub>2</sub></b> = 2-(2,4-difluorophenyl)imidazole[4,5<i>f</i>][1,10]-phenanthroline; arene = benzene, toluene, and <i>p</i>-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to <i>c-myc</i> G-quadruplex DNA through either groove binding or <i>π</i>–<i>π</i> 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 <i>c-myc</i> 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 <b>1</b> exhibited a better affinity and stability in relation to <i>c-myc</i> G-quadruplex DNA with a DC<sub>50</sub> of 6.6 μM and Δ<i>T<sub>m</sub></i> 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 <b>3</b> and <b>6</b>, 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 <b>3</b> and <b>6</b> had favorable lipid-water partition coefficients of −0.6615 and −0.8077, respectively. Moreover, it was found that complex <b>6</b> 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 <i>c-myc</i> G-quadruplex DNA to block the transcription and expression of <i>c-myc</i>. 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 <i>c-myc</i> G-quadruplex DNA, and could be used in clinical applications in the future.
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