Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China; The Marine Biomedical Research Institute, Guangdong Medical University, Zhanjiang, Guangdong 524023, PR China; The Marine Biomedical Research Institute of Guangdong Zhanjiang, Zhanjiang, Guangdong 524023, PR China.
Key Laboratory of Computer-Aided Drug Design of Dongguan City, Guangdong Key Laboratory for Research and Development of Natural Drugs, School of Pharmacy, Guangdong Medical University, Dongguan, Guangdong 523808, PR China.
J Inorg Biochem. 2023 Dec;249:112397. doi: 10.1016/j.jinorgbio.2023.112397. Epub 2023 Oct 14.
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)PPA]PF (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)PPA]PF (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)PPA]PF (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)PPA]PF (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 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.
在这项研究中，我们合成了 4 种以 N-(1,10-菲咯啉-5-基)吡啶甲酰胺（PPA）为主配体的环金属铱配合物，分别表示为 [Ir(ppy)PPA]PF（ppy=2-苯基吡啶，Ir1）、[Ir(bzq)PPA]PF（bzq=苯并喹啉，Ir2）、[Ir(dfppy)PPA]PF（dfppy=2-(3,5-二氟苯基)吡啶，Ir3）和[Ir(thpy)PPA]PF（thpy=2-(噻吩-2-基)吡啶，Ir4）。与顺铂和奥沙利铂相比，这四种配合物都表现出显著的抗肿瘤活性。其中，Ir2 对 A549 细胞的细胞毒性更高，IC 值为 1.6±0.2μM。实验结果表明，Ir2 主要定位于线粒体，诱导大量活性氧（ROS）生成，降低线粒体膜电位（MMP），减少 ATP 产生，进一步损害线粒体功能，导致细胞色素 c 释放。此外，Ir2 还通过 AKT 介导的信号通路引起细胞周期停滞在 S 期并诱导细胞凋亡。进一步研究表明，Ir2 可以同时在 A549 细胞中诱导凋亡和自噬，后者作为一种非保护性机制促进细胞死亡。更重要的是，Ir2 在体外对正常 LO2 细胞和体内斑马鱼胚胎表现出低毒性。因此，这些新开发的 Ir(III) 配合物在开发新型低毒性抗癌药物方面具有很大的潜力。
