Novel cyclometalated Ru(II) complexes containing isoquinoline ligands: Synthesis, characterization, cellular uptake and in vitro cytotoxicity

Two novel cyclometalated Ru(II) complexes containing isoquinoline ligand, [Ru(bpy)2(1-Ph-IQ)](PF6), (bpy = 2,2′-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and [Ru(phen)2(1-Ph-IQ)](PF6) (phen = 1,10-phenanthroline; RuIQ-2) were found to show high cytotoxic activity against NCI–H460, A549, HeLa and MCF-7 cell lines. Notably, both of them exhibited IC50 values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes [Ru(bpy)2(1-Py-IQ)](PF6)2 (Ru3) and [Ru(phen)2(1-Py-IQ)](PF6)2 (Ru4) (1-Py-IQ = 1-pyridine-2-yl). The cellular uptake and intracellular localization displayed that the two cyclometalated Ru(II) complexes entered NCI–H460 cancer cells dominantly via endocytosis pathway, and preferentially distributed in the nucleus. Further investigations on the apoptosis-inducing mechanisms of RuIQ-1 and RuIQ-2 revealed that the two complexes could cause S, G2/M double-cycle arrest by regulating cell cycle related proteins. The two complexes also could reduce the mitochondrial membrane potential (MMP), promote the generation of intracellular ROS and trigger DNA damage, and then lead to apoptosis-mediated cell death. More importantly, RuIQ-2 exhibits low toxicity both towards normal HBE cells in vitro and zebrafish embryos in vivo. Accordingly, the developed complexes hold great potential to be developed as novel therapeutics for effective and low-toxic cancer treatment. The cellular uptake, in vitro cytotoxicities, in vivo toxicity, cell cycle arrest and apoptosis-inducing mechanism of two new cyclometalated ruthenium(II)-isoquinoline complexes have been extensively explored by ICP-MS, MTT assay, flow cytometry, zebrafish embryos model, inverted fluorescence microscope as well as western blot experimental techniques. [Display omitted] •Two new cyclometalated Ru(II) complexes were synthesized and characterized.•RuIQ-1 and RuIQ-2 display higher activities than that of cisplatin against NCI–H460 cells.•RuIQ-2 exhibits low toxicity toward zebrafish embryos in vivo.•The mitochondrial membrane potential, ROS and DNA damage were investigated.•The cellular uptake, cell cycle arrest and apoptosis-inducing mechanism were explored.