Zhou Qin, Zhang Xiao-Bin, Liu An-Li, Niu Zhi-Gang, Li Gao-Nan, Yu Fa-Biao
Key Laboratory of Electrochemical Energy Storage and Light Energy Conversion Matreials of Haikou City, Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China; Engineering Research Center for Hainan Bio-Smart Materials and Bio-Medical Devices, Key Laboratory of Hainan Functional Materials and Molecular Imaging, College of Emergency and Trauma, Hainan Medical University, Haikou 571199, China.
Key Laboratory of Electrochemical Energy Storage and Light Energy Conversion Matreials of Haikou City, Key Laboratory of Electrochemical Energy Storage and Energy Conversion of Hainan Province, College of Chemistry and Chemical Engineering, Hainan Normal University, Haikou 571158, China.
Bioorg Chem. 2025 Jul 1;161:108507. doi: 10.1016/j.bioorg.2025.108507. Epub 2025 Apr 22.
In recent years, organo‑iridium anticancer agents have shown promising antitumor activity toward cancer cells. In this paper, two benzothiazole-based tridentate ligands, 2,2'-(5-(tert-butyl)-1,3-phenylene)bis(benzo[d]thiazole) (L) and 2,2'-(5-(methyl)-1,3-phenylene)bis(benzo[d]thiazole) (L), have been designed and synthesized, and then combined with 2,2'-bipyridine (bipy) and 1,10-phenanthroline (phen) ancillary ligands to form a series of novel [Ir(N^C^N)(N^N)Cl]-type iridium(III) complexes (Ir1-Ir4). The phosphorescence properties of these complexes facilitate the visualization of their subcellular localization and interactions with other biomolecules. Among them, complex Ir2 has the best cytotoxicity activity toward A549 cells and its antitumor activity was further evaluated. Laser confocal assay reveals that Ir2 followed an energy-dependent cellular uptake mechanism and specifically accumulates in mitochondria (Pearson colocalization coefficient: 0.89). The anticancer mechanism has been explored through apoptosis, cell cycle arrest, western blotting (WB), reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) changes. The antitumor activity in vivo confirms that Ir2 could effectively inhibit tumor growth with an inhibitory rate of 71.60 %, which is superior to cisplatin. To the best of our knowledge, Ir2 is a rare example of [Ir(N^C^N)(N^N)Cl]-type complexes as potential anticancer agents.
近年来，有机铱抗癌剂已显示出对癌细胞有良好的抗肿瘤活性。本文设计并合成了两种基于苯并噻唑的三齿配体，2,2'-(5-(叔丁基)-1,3-亚苯基)双(苯并[d]噻唑)(L)和2,2'-(5-(甲基)-1,3-亚苯基)双(苯并[d]噻唑)(L)，然后将它们与2,2'-联吡啶(bipy)和1,10-菲咯啉(phen)辅助配体结合，形成了一系列新型的[Ir(N^C^N)(N^N)Cl]型铱(III)配合物(Ir1-Ir4)。这些配合物的磷光性质有助于可视化它们在亚细胞水平的定位以及与其他生物分子的相互作用。其中，配合物Ir2对A549细胞具有最佳的细胞毒性活性，并对其抗肿瘤活性进行了进一步评估。激光共聚焦分析表明，Ir2遵循能量依赖的细胞摄取机制，并特异性地在线粒体中积累(皮尔逊共定位系数：0.89)。通过凋亡、细胞周期阻滞、蛋白质免疫印迹(WB)、活性氧(ROS)水平和线粒体膜电位(MMP)变化等方面探索了其抗癌机制。体内抗肿瘤活性证实，Ir2能有效抑制肿瘤生长，抑制率为71.60%，优于顺铂。据我们所知，Ir2是[Ir(N^C^N)(N^N)Cl]型配合物作为潜在抗癌剂的罕见例子。
