The incorporation of an organelle-targeting moiety into compounds has proven to be an effective strategy in the development of targeted anticancer drugs. We herein report the synthesis, characterization, and biological evaluation of novel triphenylphosphine-modified half-sandwich iridium^III, rhodium^III, and ruthenium^II complexes. The primary goal was to enhance anticancer selectivity through mitochondrial targeting. All these triphenylphosphine-modified complexes exhibited promising cytotoxicity in the micromolar range (5.13–23.22) against A549 and HeLa cancer cell lines, surpassing the activity of comparative complexes that lack the triphenylphosphine moiety. Noteworthy is their good selectivity toward cancer cells compared to normal BEAS-2B cells, underscored by selectivity index ranging from 7.3 to >19.5. Mechanistically, these complexes primarily target mitochondria rather than interacting with DNA. The targeting of mitochondria and triggering mitochondrial dysfunction were confirmed using both confocal microscopy and flow cytometry. Their ability to depolarize mitochondrial membrane potential (MMP) and enhance reactive oxygen species (ROS) was observed, thereby leading to intrinsic apoptotic pathways. Moreover, these complexes lead to cell cycle arrest in the G₂/M phase and demonstrated antimigration effects, significantly inhibiting the migration of A549 cells in wound-healing assays.

中文翻译：

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三苯基膦修饰的铱 III、铑 III 和钌 II 复合物通过靶向线粒体实现增强的抗癌选择性


将细胞器靶向部分掺入化合物已被证明是开发靶向抗癌药物的有效策略。我们在此报告了新型三苯基膦修饰的半夹心铱^III、铑^III 和钌^II 配合物的合成、表征和生物学评价。主要目标是通过线粒体靶向增强抗癌选择性。所有这些三苯基膦修饰的复合物在微摩尔范围 （5.13–23.22） 对 A549 和 HeLa 癌细胞系表现出有希望的细胞毒性，超过了缺乏三苯膦部分的比较复合物的活性。值得注意的是，与正常 BEAS-2B 细胞相比，它们对癌细胞具有良好的选择性，选择性指数范围为 7.3 至 >19.5。从机制上讲，这些复合物主要靶向线粒体，而不是与 DNA 相互作用。使用共聚焦显微镜和流式细胞术证实了线粒体的靶向和触发线粒体功能障碍。观察到它们去极化线粒体膜电位 （MMP） 和增强活性氧 （ROS） 的能力，从而导致内在的凋亡途径。此外，这些复合物导致细胞周期停滞在 G₂/M 期，并显示出抗迁移作用，在伤口愈合试验中显着抑制 A549 细胞的迁移。