Cancer remains a significant global health challenge due to its high morbidity and mortality rates, presenting an urgent problem for scientists and clinicians. In recent years, metal-based anticancer agents, particularly cisplatin analogues, have shown significant promise in cancer treatment [[1], [2], [3]]. However, their clinical use is hindered by toxicity and resistance issues, driving researchers to explore new metal-based therapeutics with improved profiles [4,5]. As a result, the design and development of novel metal-based anticancer drugs with potent cytotoxicity and innovative mechanisms of action (MoAs) have become a key focus for researchers in both academic and commercial sectors [[6], [7], [8], [9]]. Extensive studies have been conducted on platinum group metal complexes (e.g., Ru, Rh, Os, Ir), with ruthenium complexes such as KP1019 and NAMI-A showing particularly promising results in both preclinical and clinical trials [10,11].

Compared to traditional platinum-based anticancer drugs, half-sandwich metal complexes, with their unique structural design, offer the ability to regulate biological activity while maintaining chemical stability [[12], [13], [14], [15]]. In recent years, half-sandwich organometallic anticancer complexes of platinum group metals, with the formula [(η5-Cpx)/(η6-arene)M(XY)Z]0/+ (Cpx = substituted cyclopentadienyl ring, XY = bidentate ligand, Z = monodentate labile ligand such as Cl−, M = Ru, Rh, Os, Ir,), have recently gained attention as a versatile platform for developing anticancer agents due to their unique coordination properties and mechanisms of actions (MoAs) [[16], [17], [18]]. The main focus has been on the study of cationic or neutral complexes, using a variety of bidentate XY chelating ligands, with special emphasis on N,N-donor systems. One notable example is the arene‑rutheniumII complex RM175, which incorporates an ethylenediamine (en) ligand (Scheme 1I) [19]. RM175 has shown significant cytotoxic effects in vitro and in vivo studies. Notably, it displayed no cross-resistance in cisplatin-resistant A2780cis cells, suggesting a unique mechanism of action [20,21]. Furthermore, iridiumIII complexes with N,N-chelating bipyridine (bpy) ligands, as reported by the Sadler group, have shown nearly twice the anticancer efficacy of cisplatin against A2780 cells (Scheme 1II) [22]. The improved anticancer activity is linked to greater hydrophobicity and stronger DNA-binding affinity. Our group has advanced the design of platinum group-based half-sandwich complexes with N,N-chelating ligands. Notably, pyridyl-imine rutheniumII and iridiumIII complexes (Scheme 1III and IV) have shown the capability to catalyze NADH oxidation to NAD+, elevate reactive oxygen species (ROS) levels, compromise mitochondrial membrane potential (MMP), and demonstrate strong cytotoxic effects against A549 and HeLa cancer cell lines [[23], [24], [25]]. Under oxidative stress from high ROS levels, cancer cells are sensitive to redox changes. Some pyridyl-imine rutheniumII complexes showed selectivity for A549 cells over BEAS-2B cells (Scheme 1IV) [24,25]. A series of rutheniumII and iridiumIII complexes featuring α-diimine N,N-chelating ligands were successfully synthesized (Scheme 1V and VI). The mechanism underlying the activity of such metal complexes has been thoroughly investigated by our group [[26], [27], [28]]. These compounds trigger apoptosis via ROS-mediated pathways and exhibit no cross-resistance with cisplatin.

Mitochondria are essential for energy production, apoptosis, and redox regulation [26]. In cancer cells, mitochondrial dysfunction is often observed, characterized by the disrupted energy metabolism, increased oxidative stress and elevated mitochondrial membrane potential (MMP). These abnormalities enable targeted therapy against cancer cell mitochondria for better outcomes [[30], [31], [32]]. Mitochondria-targeting drugs generally possess high positive charge and strong lipophilicity [33,34]. The elevated MMP in cancer cells enhances the accumulation of lipophilic cations within their mitochondria, distinguishing them from normal cells [35,36]. Furthermore, lipophilic anticancer agents can interfere with cellular metabolic equilibrium and ROS regulation through their interactions with mitochondrial membranes [37,38].

The N,N-chelating complexes discussed above can be divided into two coordination types: amine (sp3-N/sp3-N)-metal (Scheme 1I) and imine (sp2-N/sp2-N)-metal (Scheme 1II–VI). We further expanded our study to include hybrid sp3-N/sp2-N chelating complexes, resulting in the synthesis of amine-imine (sp3-N/sp2-N) half-sandwich rutheniumII and iridiumIII complexes (Scheme 1VII and VIII) [29]. The rutheniumII complexes, classified as 18-electron, six-coordinated structures (Scheme 1VII), and the iridiumIII counterparts, defined as 16-electron, five-coordinated systems lacking monodentate labile Cl− (Scheme 1VIII), exhibited notably distinct coordination patterns. These complexes exhibited notable cytotoxicity and cisplatin cross-resistance, potentially attributable to a redox-mediated mitochondrial pathway. These encouraging preliminary results inspire us to further explore novel sp3-N/sp2-N-based complexes. By reducing our previously reported diimine (sp2-N/sp2-N) ligand (Scheme 1V and VI) to an amine-imine structure, we successfully synthesized a new series of half-sandwich amine-imine (sp3-N/sp2-N) rutheniumII and iridiumIII complexes (Scheme 1, This work). All the complexes in this study exhibited significant activity against several cancer cell lines, demonstrating cytotoxicity superior to both the corresponding α-diimine complexes and cisplatin. Furthermore, their potential mechanisms of actions (MoAs) were investigated in vitro, focusing on cellular targeting, ROS production, and apoptosis induction.