在这里，我们设计、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)。对 2D 和 3D 多细胞肿瘤球体 (MCTS) 进行的细胞毒性实验表明，与配体和前体化合物以及临床顺铂相比，复合物 RuIQ9-11 对 A549 和 A549/DDP 细胞表现出明显更高的细胞毒性。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，复合物 RuIQ9-11 可以通过引起细胞周期停滞、线粒体功能障碍和升高 ROS 水平诱导这些细胞凋亡来抑制 A549 和 A549/DDP 细胞迁移和增殖。机制研究表明，RuIQ9-11可以通过抑制耐药A549/DDP细胞中Nrf2基因转录来抑制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，确保复合物在细胞内积累。这导致耐药细胞的细胞内ROS水平增加，最终造成损伤和细胞死亡，从而克服顺铂耐药性。更重要的是，RuIQ11可以有效抑制斑马鱼体内耐药细胞的迁移和增殖，解决顺铂耐药问题。因此，所制备的 Ru(II) 配合物具有作为高效、低毒性肺癌治疗剂克服顺铂耐药性的巨大潜力。版权所有 © 2024 Elsevier Inc. 保留所有权利。

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.Copyright © 2024 Elsevier Inc. All rights reserved.