Development of four ruthenium polypyridyl complexes as antitumor agents: Design, biological evaluation and mechanism investigation.

Ruthenium complexes are expected to be new opportunities for the development of antitumor agents. Herein, four ruthenium polypyridyl complexes ([Ru(bpy)2(CAPIP)](ClO4)2 (Ru(II)-1, bpy = 2,2'-bipyridine; CAPIP = (E)-2-(2-(furan-2-yl)vinyl)-1H-imidazo[4,5-f][1,10]phenanthroline), [Ru(phen)2(CA-PIP)](ClO4)2 (Ru(II)-2, phen = 1,10-phenanthroline), [Ru(dmb)2(CAPIP)](ClO4)2 (Ru(II)-3, dmb = 4,4'-dimethyl-2,2'-bipyridine), [Ru(dmb)2(ETPIP)](ClO4)2 (Ru(II)-4, ETPIP = 2-(4-(thiophen-2-ylethynyl)phenyl)-1H-imidazo[4,5-f][1,10]phen-anthroline)) have been investigated as mitochondria-targeted antitumor metallodrugs. DNA binding studies indicated that target Ru(II) complexes interacts with CT DNA (calf thymus DNA) by an intercalative mode. Cytotoxicity assay results demonstrate that Ru(II) complexes show high cytotoxicity against A549 cells with low IC50 value of 23.6 ± 2.3, 20.1 ± 1.9, 22.7 ± 1.8 and 18.4 ± 2.3 μM, respectively. Flow cytometry and morphological analysis revealed that these Ru(II) complexes can induce apoptosis in A549 cells. Intracellular reactive oxygen species (ROS) and mitochondrial membrane potential were also investigated by ImageXpress Micro XLS system. The experimental results indicate that the reactive oxygen species in A549 cells increased significantly and mitochondrial membrane potential decreased obviously. In addition, colocalization studies shown these complexes could get to the cytoplasm through the cell membrane and accumulate in the mitochondria. Furthermore, Ru(II) complexes can effectively induces cell cycle arrest at the S phase in A549 cells. Finally, cell invasion assay and quantitative studies were also performed to investigate the mechanism of this process. All in together, this study suggested that these Ru(II) complexes could induce apoptosis in A549 cells through cell cycle arrest and ROS-mediated mitochondrial dysfunction pathway.