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

作者：Zeng, Liang; Yuan, Chanling; Shu, Jing; Qian, Jiayi; Wu, Qiong; Chen, Yanhua; Wu, Ruzhen; Ouyang, Xiaoming^*; Li, Yuan; Mei, Wenjie^*

来源：MOLECULES, 2022, 27(6): 1897.

DOI：10.3390/molecules27061897

• difluorinated ligands
• arene Ru(II) complexes
• c-myc G-quadruplex DNA

Here, a series of half-sandwich arene Ru(II) complexes with difluorinated ligands [Ru(eta(6)-arene)(L)Cl] (L-1 = 2-(2,3-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; L-2 = 2-(2,4-difluorophenyl)imidazole[4,5f][1,10]-phenanthroline; arene = benzene, toluene, and p-cymene) were synthesized and characterized. Molecular docking analysis showed that these complexes bind to c-myc G-quadruplex DNA through either groove binding or pi-pi 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 c-myc 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 1 exhibited a better affinity and stability in relation to c-myc G-quadruplex DNA with a DC50 of 6.6 mu M and Delta T-m values of 13.09 degrees 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 3 and 6, which exhibited a better inhibitory effect against human U87 glioblastoma cells (51.61 and 23.75 mu M) than other complexes, even superior to cisplatin (32.59 mu M). Owing to a befitting lipophilicity associated with the high intake of drugs by tumor cells, complexes 3 and 6 had favorable lipid-water partition coefficients of -0.6615 and -0.8077, respectively. Moreover, it was found that complex 6 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 c-myc G-quadruplex DNA to block the transcription and expression of c-myc. 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 c-myc G-quadruplex DNA, and could be used in clinical applications in the future.

• 单位
  广东药学院; 广州医学院