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)(1-Ph-IQ), (bpy = 2,2'-bipyridine; 1-Ph-IQ = 1-phenylisoquinoline; RuIQ-1) and Ru(phen)(1-Ph-IQ) (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 IC values that were an order of magnitude lower than those of clinical cisplatin and two structurally similar Ru(II)-isoquinoline complexes Ru(bpy)(1-Py-IQ) (Ru3) and Ru(phen)(1-Py-IQ) (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.