Polypyridyl Ruthenium(II) complex-induced mitochondrial membrane potential dissipation activates DNA damage-mediated apoptosis to inhibit liver cancer

In this study, four polypyridyl ruthenium(II) complexes, namely, [(L1)2RuL2]·2ClO4 (1: L1 = phen, L2 = o-TFPIP, 2: L1 = bpy, L2 = o-TFPIP, 3: L1 = phen, L2 = o-MOPIP, and 4: L1 = bpy, L2 = o-MOPIP), were synthesized with different phenanthroimidazole derivatives, and their inhibitory activities were tested against various cancer cells. Among the Ru(II) complexes, 1 excellently inhibited the proliferation and induced the apoptosis of HepG2 cell. Importantly, 1 was mainly distributed in the cell mitochondria and markedly induced the dissipation of mitochondrial membrane potential, possibly attributing to DNA damage induced by the Ru(II) complexes. Synthetic Ru(II) complexes can suppress the growth of tumor cells in zebrafish xenograft model with low toxicity at effective concentrations. These results inspired us to further develop polypyridyl ruthenium(II) complexes as potential potent inhibitors against liver cancer.