In vitro evaluation of cytotoxicity and antimetastatic properties of novel arene ruthenium(II)-tetrazolato compounds on human cancer cell lines

Abstract

Two new arene ruthenium(II) complexes with chemical formula [Ru2(η6-p-cymene)2(μ-L1)(μ-Cl)Cl2] [Ru]-1 and [Ru(η6-p-cymene)(L2)Cl2] [Ru]-2 (L1 = 5-phenyl-2H-tetrazole and L2 = 2-(2H-tetrazol-5-yl)pyridine) were synthesized by the reaction of [{(η6-p-cymene)RuCl2}2] with two bidentate ligands L1 and L2. Both the complexes were structurally characterized using single-crystal X-ray diffraction and other analytical techniques. The X-ray crystal structures of both the complexes revealed the coordination of tetrazolate ligands to two Ru(II) centres in bridging mode in [Ru]-1, whereas one Ru(II) centre in [Ru]-2 in chelating fashion, with overall pseudo-octahedral geometry. The resulted complexes were screened for their cytotoxic activity against three different cancer cell lines, HCT116 (colon cancer), HepG2 (liver cancer) and MCF7 (breast cancer) under in vitro conditions. Interestingly, [Ru]-1 showed much higher cytotoxicity with respect to [Ru]-2 against all the screened cancer cell lines and even better than cisplatin. For exploring the mechanism of action of [Ru]-1, reactive oxygen species (ROS) production, alterations in mitochondrial membrane potential and gene expression profiling of apoptosis related genes (Bcl2, caspase-3 and caspase-9) were also evaluated. The cancerous cells treated with [Ru]-1 showed an increase in intracellular ROS levels, disruption of mitochondrial membrane potential, up-regulation of proapoptotic caspase-3 and caspase-9 and down-regulation of antiapoptotic Bcl2. The results concluded that [Ru]-1 induced apoptosis through oxidative stress mediated activation of intrinsic pathway by generating intracellular ROS, loss of MMP and alteration of expression of apoptosis related genes. In addition, antimetastatic activity of [Ru]-1 was observed by wound healing assay showing anti-migratory property. The dual properties, antimetastatic activity and high cytotoxicity make [Ru]-1 potent platform for the development of new anticancer agents. © 2021 John Wiley & Sons, Ltd.