基于其强大的抗癌特性，定位于线粒体的环金属铱配合物显示出作为铂系配合物替代品的巨大潜力。本研究通过合成并对五种不同细胞系中的三种新型环金属铱(III)化合物进行评估，以作为这些化合物系统研究的一部分。这些配合物是使用4,7-二氯-1,10-菲啰啉配体制备的。结果显示，配合物Ir1-Ir3对HeLa细胞的细胞毒性较高，分别具有IC50值为0.83±0.06、4.73±0.11和4.95±0.62μM。配合物Ir1能在3小时内被HeLa细胞摄入，并显示出较高的线粒体选择性。随后的研究表明，Ir1通过增加活性氧的产生、减少线粒体膜电位和降低三磷酸腺苷(ATP)水平来诱导HeLa细胞凋亡。此外，对Ir1的处理导致了细胞运动的显著抑制，并阻滞了细胞周期在G0/G1期的进展。Western blot分析显示，在HeLa细胞中，Ir1诱导的凋亡涉及到线粒体相关通道和PI3K/AKT信号通路的活化。在浓度小于或等于16µM的情况下，对斑马鱼胚胎没有观察到明显的细胞毒性，如存活率和发育异常。体内实验证明，Ir1抑制了小鼠的肿瘤生长。因此，我们的研究显示，化合物Ir1可能是发展新型抗肿瘤药物的有前途的候选物。Copyright © 2023 Elsevier Inc. 版权所有。

Cyclometalated iridium complexes with mitochondrial targeting show great potential as substitutes for platinum-based complexes because of their strong anti-cancer properties. Three novel cyclometalated iridium(III) compounds were synthesized and evaluated in five different cell lines as part of the ongoing systematic investigations of these compounds. The complexes were prepared using 4,7-dichloro-1,10-phenanthroline ligands. The cytotoxicity of complexes Ir1-Ir3 towards HeLa cells was shown to be high, with IC50 values of 0.83±0.06, 4.73±0.11, and 4.95±0.62 μM, respectively. Complex Ir1 could be ingested by HeLa cells in 3 h and has shown high selectivity toward mitochondria. Subsequent investigations demonstrated that Ir1 triggered apoptosis in HeLa cells by augmenting the generation of reactive oxygen species (ROS), reducing the mitochondrial membrane potential, and depleting ATP levels. Furthermore, the movement of cells was significantly suppressed and the progression of the cell cycle was arrested in the G0/G1 phase following the administration of Ir1. The Western blot analysis demonstrated that the induction of apoptosis in HeLa cells by Ir1 involves the activation of the mitochondria-dependent channel and the PI3K/AKT signaling pathway. No significant cytotoxicity was observed in zebrafish embryos at concentrations less than or equal to 16 µM, e.g., survival rate and developmental abnormalities. In vivo, antitumor assay demonstrated that Ir1 suppressed tumor growth in mice. Therefore, our work shows that complex Ir1 could be a promising candidate for developing novel antitumor drugs.Copyright © 2023 Elsevier Inc. All rights reserved.