Abstract
Two new Ru(II) complexes containing O, O-chelated ligands, Ru(dip)2(SA) (Ru-1) and Ru(dmp)2(SA) (Ru-2) (dip = 4,7-diphenyl-1,10-phenanthroline; dmp = 2,9-dimethyl-1,10-phenanthroline; SA = salicylate) were synthesized to evaluate their cytotoxicity in vitro. These complexes were found to exhibit moderate antitumor activity to different types of human cancers, including A549 (human lung carcinoma), MCF-7 (breast cancer), HeLa (human cervical cancer), and HepG2 (human hepatocellular carcinoma) cell lines, but displayed low toxicity to human normal cell lines BEAS-2B (immortalized human bronchial epithelial cells) when compared with that of cisplatin. Further studies revealed that these complexes could induce apoptosis in A549 cells, including activating caspase family proteins and poly (ADP-ribose) polymerase (PARP), reducing Bcl-2/Bax and Bcl-xl/Bad ratio, enhancing cellular reactive oxygen species (ROS) accumulation, triggering DNA damage, decreasing mitochondrial membrane potential (MMP), and leading cytochrome c release from mitochondria. Notably, complex Ru-1 showed low toxicity to developing zebrafish embryos. The obtained results suggest that these new synthetic complexes have the potential to be developed as low-toxicity agents for lung cancer treatment.
Highlights
As a new class of nonplatinum metal complexes, rutheniumbased compounds possess valuable photophysical and photochemical properties and high structural diversity, which provide more direction for designing new ruthenium anticancer drugs [1, 2]
Complexes Ru-1 and Ru-2 were synthesized by the reaction of cis-[Ru(N-N)2Cl2] (N-N dip, dmp) and salicylic acid in the presence of sodium hydroxide. e crude product was purified by chromatography over alumina. e obtained compounds were analyzed by elemental analysis, Electrospray ionization mass spectrometry (ESI-MS), 1H NMR, Fourier Transform infrared (FTIR), and UV-Vis absorption spectroscopy, and the results were shown in Figures S1–S7 in Supplementary Materials. e stability of Ru-1 and Ru-2 in water and CH3CN solution at 298 K was analyzed by UV-Vis absorption spectroscopy (Figures S3–S5)
Our study extensively evaluated the anticancer effect of two novel Ru(II) complexes containing O, O-chelated ligands in A549 human lung cancer cells, which was mediated through inducing cell apoptosis
Summary
As a new class of nonplatinum metal complexes, rutheniumbased compounds possess valuable photophysical and photochemical properties and high structural diversity, which provide more direction for designing new ruthenium anticancer drugs [1, 2]. Chen et al pointed out that the selection of ligands plays a key role in the antitumor cell selectivity, targeting, antitumor activity, and mechanism of ruthenium compounds [3]. Toledano-Magaña et al reported a series of neutral Ru(II) complexes containing anionic O, O-chelating ligands (acetylacetonate derivatives), and their studies suggested some of these compounds possessed reasonable activity towards A2780 cells [13]. Bezerra and his partners synthesized some piplartine-containing ruthenium complexes and investigated the apoptosis inducing effect in human colon carcinoma HCT116 cells and underlying mechanisms by these ruthenium complexes-induce cell death [14, 15]. We have synthesized three O, O-chelated ligand-bearing Ru(II) complexes, which are [Ru(bpy)2(SA)] (SA salicylate), [Ru(phen)2(SA)] and [Ru(dmb)2(SA)], and found that these complexes induced apoptosis in A549 cells by targeting TrxR [16]
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