Synthesis and anticancer properties of ruthenium (II) complexes as potent apoptosis inducers through mitochondrial disruption

A new ligand MHPIP (MHPIP =2-(1-methyl-1H-pyrazol-4-y1)-1H-imidazo[4,54][1,10]phenanthroline) and its three ruthenium (II) complexes [Ru(N-N)(2)(MHPIP)1(Cio(4))2 (N -N = phen: 1,10-phenanthroline 1; dmp = 2,9-dimethyl-1,10-phenanthroline 2; ttbpy = 4,4'-ditertiarybutyl-2,2'-bipyridine 3) were synthesized and characterized. The cytotoxic activity in vitro was studied by MTT method. The complexes 1 3 show moderate cytotoxic effects on the cell growth in HepG(2) cells with an IC50 value of 25.5 +/- 3.5, 35.6 +/- 1.9 and 27.4 +/- 2.3 respectively. The apoptosis was investigated with AO/EB and Annex V/PI staining methods and comet assay. The reactive oxygen species, mitochondrial membrane potential were investigated under a fluorescent microscope. Autophagy assay shows that the complexes can cause autophagy and up -regulate the expression of Beclin-1 protein. Additionally, the complexes inhibit the cell growth in HepG(2) cells at G0/G1 phase, and the complexes can regulate the expression of caspase 3 and Bc1-2 family, proteins. The studies demonstrate that the complexes induce apoptosis in HepG2 cells through DNA damage and ROS-mediated mitochondrial dysfunction pathways. (C) 2017 Published by Elsevier Masson SAS.