Exploring a novel asymmetric tris-heteroleptic iridium(III) complex as mitochondria-targeted anticancer agents

Author links open overlay panelAn-Li Liu a b,Si-Yu Chen a b,Qin Zhou a,Fa-Biao Yu b,Gao-Nan Li a,Zhi-Gang Niu a

• aKey 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

• bEngineering 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 17 July 2025, Revised 18 September 2025, Accepted 5 October 2025, Available online 6 October 2025, Version of Record 12 October 2025.

Journal of Inorganic Biochemistry

Volume 274, January 2026, 113102

https://doi.org/10.1016/j.jinorgbio.2025.113102

Highlights

• •Three piq/btp-based bis/tris-heteroleptic Ir(III) complexes were synthesized.

  •Their photophysical properties and cytotoxic activities in vitro were investigated.

• •The anticancer mechanism and antitumor activity of novel complex Ir2 were studied.

• Abstract

Organometallic iridium(III) complexes are a highly promising class of metal-based anticancer agents. In this study, three bis−/tris-heteroleptic iridium(III) complexes–[Ir(piq)2(bpy)]PF6 (Ir1), [Ir(piq)(btp)(bpy)]PF6 (Ir2) and [Ir(btp)2(bpy)]PF6 (Ir3)–were synthesized and characterized, where piq = 1-phenylisoquinoline, btp = 2-(benzothienyl)pyridine and bpy = 2,2′-bipyridine. Their photophysical properties were studied, and theoretical calculations were conducted to better understand the variations along the series. All complexes exhibited potent cytotoxicity against tumor cells, among which tris-heteroleptic complex Ir2 showed superior activity toward HeLa cells–prompting comprehensive antitumor studies of this complex. Laser confocal assay revealed that Ir2 entered cells via an energy-dependent uptake mechanism while exhibiting specific mitochondrial targeting, as evidenced by a high Pearson's colocalization coefficient (PCC = 0.93). Subsequent biological assays–including apoptosis analysis, cell cycle arrest, reactive oxygen species (ROS) levels and mitochondrial membrane potential (MMP) changes–revealed that complex Ir2 induced HeLa cells apoptosis through mitochondrial dysfunction. The antitumor activity in vivo confirmed that Ir2 could effectively suppressed tumor growth in HeLa xenograft-bearing mice (61.80 % inhibition) without adverse effects on major organs. Overall, complex Ir2 represents a novel asymmetric tris-heteroleptic iridium(III) complex developed for anticancer applications, with results demonstrating its excellent antitumor efficacy, thereby positioning its potential as a new alternative to conventional anticancer agents.

Graphical abstract

A novel asymmetric tris-heteroleptic iridium(III) complex Ir2 was explored as anticancer agents, which exhibited potent anticancer activity against HeLa cells both in vitro and in vivo by activating mitochondrial apoptosis pathways.

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