Department of Pathology, Guangzhou Women and Children's Medical Center, Guangzhou Medical University, Guangzhou 510623, China.
School of Pharmacy, Guangdong Pharmaceutical University, Guangzhou 510006, China.
Molecules. 2022 Mar 15;27(6):1897. doi: 10.3390/molecules27061897.
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.
这里，我们合成并表征了一系列带有氟化配体的半三明治芳基金属钌（II）配合物[Ru(-芳烃)(L)Cl]（ = 2-(2,3-二氟苯基)咪唑[4,5][1,10]-菲咯啉； = 2-(2,4-二氟苯基)咪唑[4,5][1,10]-菲咯啉；芳烃 = 苯、甲苯和 - 枯烯）。分子对接分析表明，这些配合物通过沟槽结合或 - 堆积与 G-四链体 DNA 结合，而主配体中相对氟化位置在调节结合模式方面发挥作用。使用紫外-可见光谱、荧光插层剂置换分析、荧光共振能量转移熔融分析和聚合酶链反应评估了这些配合物与 G-四链体 DNA 的结合行为。综合分析表明，配合物 与 G-四链体 DNA 的亲和力和稳定性较好，其 DC 为 6.6 μM，Δ 值为 13.09°C，优于其他分子。进一步的活性评价结果表明，这类配合物还可以抑制各种肿瘤细胞的生长，尤其是配合物 和 ，它们对人 U87 神经胶质瘤细胞的抑制作用（51.61 和 23.75 μM）优于其他配合物，甚至优于顺铂（32.59 μM）。由于与肿瘤细胞摄取药物相关的适当亲脂性，配合物 和 具有良好的脂水分配系数，分别为-0.6615 和-0.8077。此外，研究发现配合物 主要通过诱导明显的 S 期阻滞和轻微的细胞凋亡来抑制 U87 细胞的增殖，这可能是由于 G-四链体 DNA 的稳定，从而阻断了 的转录和表达。总之，这些带有氟化配体的芳基金属钌（II）配合物可以作为通过结合和稳定 G-四链体 DNA 诱导 S 期阻滞和凋亡的潜在诱导剂，将来可用于临床应用。
