Natural products and metals play a crucial role in cancer research and the development of antitumor drugs. We designed and synthesized three new carboline-based cyclometalated iridium complexes [Ir(C-N)2(PPβC)](PF6), where PPβC = N-(1,10-phenanthrolin-5-yl)-1-phenyl-9H-pyrido[3,4-b]indole-3-carboxamide, C-N = 2-phenylpyridine (ppy, Ir1), 2-(2,4-difluorophenyl) pyridine (dfppy, Ir2), 7,8-benzoquinoline (bzq, Ir3), by combining iridium with β-carboline derivative. These iridium complexes exhibited high potential antitumor effects after being promptly taken up by A549 cells. Accumulating in mitochondria rapidly and preferentially, Ir1-3 caused a series of changes in mitochondrial events, including the loss of mitochondrial membrane potential, the depletion of cellular ATP, and the elevation of reactive oxygen species, leading to significant death of A549 cells. Moreover, the activation of intracellular caspase pathway and apoptosis was further validated to contribute to iridium complexes-induced cytotoxicity. These novel iridium complexes exerted a prominent inhibitory effect on tumor growth in a three-dimensional multicellular tumor spheroid model.

中文翻译：

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线粒体靶向环金属化铱-β-咔啉复合物作为有效的非小细胞肺癌治疗剂。

天然产物和金属在癌症研究和抗肿瘤药物的开发中发挥着至关重要的作用。我们设计并合成了三种新型咔啉基环金属化铱配合物[Ir(CN)2(PPβC)](PF6)，其中PPβC = N-(1,10-菲咯啉-5-基)-1-苯基-9H-吡啶并[3,4-b]吲哚-3-甲酰胺，CN = 2-苯基吡啶（ppy，Ir1），2-（2,4-二氟苯基）吡啶（dfppy，Ir2），7,8-苯并喹啉（bzq，Ir3） ，通过将铱与β-咔啉衍生物结合。这些铱配合物在被 A549 细胞迅速摄取后表现出很高的潜在抗肿瘤作用。Ir1-3在线粒体中快速且优先地积累，引起线粒体事件的一系列变化，包括线粒体膜电位的丧失、细胞ATP的耗尽以及活性氧的升高，导致 A549 细胞显着死亡。此外，进一步验证了细胞内半胱天冬酶途径和细胞凋亡的激活有助于铱复合物诱导的细胞毒性。这些新型铱配合物在三维多细胞肿瘤球体模型中对肿瘤生长具有显着的抑制作用。