Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy.

In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy) 2 PPA]PF 6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq) 2 PPA]PF 6 (bzq = benzo[ h ]quinoline, Ir2), [Ir(dfppy) 2 PPA]PF 6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy) 2 PPA]PF 6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC 50 value of 1.6 ± 0.2 μM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents. Four new cyclometalated iridium complexes Ir1-Ir4 were prepared and exhibited excellent cytotoxic activity. Complex Ir2 induced cell cycle arrest, mitochondrial dysfunction, apoptosis and autophagy. Complex Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. [Display omitted] • Four new cyclometalated Ir(III) complexes Ir1-Ir4 were prepared and exhibited excellent cytotoxic activity. • Ir2 preferentially accumulated in mitochondria and caused a series of changes in mitochondrial events. • Complexes Ir1-Ir4 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. • Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells. [ABSTRACT FROM AUTHOR]