这里,我们设计的,合成并表征了三种新的环金属化Ru(II)配合物,[Ru(phen)2(1-(4-Ph-Ph)-IQ)](phen=1,10-菲咯啉,IQ=异喹啉,RuIQ9),[Ru(phen)2(1-(4-Ph-Ph)-7-OCH3-IQ)]+(RuIQ10),和[Ru(phen)2(1-(4-Ph-Ph)-6,7-(OCH3)2-IQ)]+(RuIQ11)。在2D和3D多细胞肿瘤球体(MCTSs)上进行的细胞毒性实验表明,当与配体和前体化合物以及临床顺铂相比时,复合物RuIQ9-11表现出对A549和A549/DDP细胞的显著更高的细胞毒性。此外,在体外对正常HBE细胞进行测试并在体内暴露于斑马鱼胚胎时,Ru(II)复合物显示出低毒性。此外,RuIQ9-11复合物可以通过引起细胞周期阻滞来抑制A549和A549/DDP细胞的迁移和增殖,线粒体功能障碍,并提高ROS水平以诱导这些细胞的凋亡。机制研究表明,RuIQ9-11可以通过抑制耐药A549/DDP细胞中Nrf2基因的转录来抑制Nrf2及其下游抗氧化蛋白HO-1的表达。同时,它们抑制耐药细胞中外排蛋白MRP1和p-gp的表达,确保细胞内复合物的积累。这导致耐药细胞中细胞内ROS水平增加,最终造成损伤和细胞死亡,从而克服顺铂耐药。更重要的是,RuIQ11能有效抑制斑马鱼体内耐药细胞的迁移和增殖,解决顺铂耐药的问题。因此,所制备的Ru(II)配合物具有作为克服顺铂耐药性的高效低毒肺癌治疗剂的巨大发展潜力。
Here, we designed, synthesized and characterized three new cyclometalated Ru(II) complexes, [Ru(phen)2(1-(4-Ph-Ph)-IQ)]+ (phen = 1,10-phenanthroline, IQ = isoquinoline, RuIQ9), [Ru(phen)2(1-(4-Ph-Ph)-7-OCH3-IQ)]+ (RuIQ10), and [Ru(phen)2(1-(4-Ph-Ph)-6,7-(OCH3)2-IQ)]+ (RuIQ11). The cytotoxicity experiments conducted on both 2D and 3D multicellular tumor spheroids (MCTSs) indicated that complexes RuIQ9-11 exhibited notably higher cytotoxicity against A549 and A549/DDP cells when compared to the ligands and precursor compounds as well as clinical cisplatin. Moreover, the Ru(II) complexes displayed low toxicity when tested on normal HBE cells in vitro and exposed to zebrafish embryos in vivo. In addition, complexes RuIQ9-11 could inhibit A549 and A549/DDP cell migration and proliferation by causing cell cycle arrest, mitochondrial dysfunction, and elevating ROS levels to induce apoptosis in these cells. Mechanistic studies revealed that RuIQ9-11 could suppress the expression of Nrf2 and its downstream antioxidant protein HO-1 by inhibiting Nrf2 gene transcription in drug-resistant A549/DDP cells. Simultaneously, they inhibited the expression of efflux proteins MRP1 and p-gp in drug-resistant cells, ensuring the accumulation of the complexes within the cells. This led to an increase in intracellular ROS levels in drug-resistant cells, ultimately causing damage and cell death, thus overcoming cisplatin resistance. More importantly, RuIQ11 could effectively inhibit the migration and proliferation of drug-resistant cells within zebrafish, addressing the issue of cisplatin resistance. Accordingly, the prepared Ru(II) complexes possess significant potential for development as highly effective and low-toxicity lung cancer therapeutic agents to overcome cisplatin resistance.