Designing novel tridentate iridium(III) complexes comprising functionalized benzothiazole ligands to improve anticancer activity by targeting mitochondria☆
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- 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
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- Key Laboratory of Emergency and Trauma, Ministry of Education, Key Laboratory of Haikou Trauma, Key Laboratory of Hainan Trauma and Disaster Rescue, The First Affiliated Hospital, Hainan Medical University, Haikou 571199, China
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- 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
Received 8 March 2025, Revised 11 April 2025, Accepted 21 April 2025, Available online 22 April 2025, Version of Record 25 April 2025.
https://doi.org/10.1016/j.bioorg.2025.108507
Highlights
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A series of mitochondrial-targeted iridium(III) complexes with functionalized benzothiazole tridentate ligands were synthesized.
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The photophysical properties and cytotoxic activities in vitro of these iridium(III) complexes were investigated.
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The anticancer mechanism in A549 cells and antitumor activity in vivo of complex Ir2 were studied and evaluated, respectively.
Abstract
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) (L1) and 2,2′-(5-(methyl)-1,3-phenylene)bis(benzo[d]thiazole) (L2), 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.
Fig. 4. (a) Confocal images of A549 cells treated with Ir2 at 37 °C or 4 °C, and then incubated with CCCP or chloroquine at 37 °C. (b) Colocalization images of Ir2 with MTDR and LTDR in A549 cells. Ir2: λex = 445 nm, λem = 520 ± 30 nm; MTDR: λex = 561 nm, λem = 600 ± 30 nm; LTDR: λex = 594 nm, λem = 630 ± 30 nm. Scale bar: 50 μm.
Fig. 9. Photographs of tumor in vivo (a), tumor sizes (b) and tumor weight (c) in control and cisplatin/Ir2-treated groups (3.0 mg/kg) at the end of treatment. The tumor volume (d) and changes in body weight (e) of each group throughout the follow-up period. The data are the mean of three replicate experiments ± SD.
