In recent years, medicinal chemistry has made significant strides in exploring metal-based drug candidates across the periodic table [[1], [2], [3], [4]]. The clinical application of platinum-based anticancer drugs has been hindered by their undesirable side effects, prompting scientists to explore alternative metallodrugs with anticancer potential [[5], [6], [7]]. Ruthenium (Ru) and iridium (Ir) complexes have garnered significant attention and have undergone extensive investigation at various stages of clinical trials as potential chemotherapeutic agents [[8], [9], [10]]. Particularly, Ru and Ir-arene complexes have emerged as focal points due to their specificity towards cancer cells, facile modification, minimal side effects, and diverse mechanisms of action. The anticancer activity of Ru/Ir-arene complexes often stems from their ability to interact with biomolecules, including DNA and proteins. Additionally, they may induce oxidative stress by generating reactive oxygen species (ROS), triggering apoptosis in cancer cells.

Taking account of the intriguing catalytic property of organometallics, Zhao [11] rationally designed the first ruthenium(II)-affibody catalyst hybrid for in situ prodrug activation and selectively killing HER2-positive cancer cells.

Li [12] synthesized half-sandwich metal complexes with imino-triphenylpyridine ligands. Their iridium and ruthenium complexes exhibit potent anticancer efficacy and luminescence, paving the way for advanced theranostic systems. Xu [13] has integrated D-A-D groups with NIR absorption into aryl ruthenium(II) complexes, enabling self-assembly into supramolecular structures for synergistic photothermal and photodynamic therapy under 808 nm NIR irradiation. Liu [14] synthesized an innovative semi-sandwich organoiridium(III) complex with a pyridine ligand, demonstrating superior cytotoxicity to chloride analogs and cisplatin in cancer cell lines. The ligand confers resistance to glutathione-mediated degradation, correlating with elevated ROS levels in cancer cells, positioning the complex as a potential lead in oxidative cancer therapeutics.

Moreover, our group proposed the metal-ligand synergistic enhancement (MLSE) strategy by the combination of metal centers with natural products to enhance the chemotherapy effect and activate specific tumor immunity of metal-based anticancer agents [7,10,[15], [16], [17]]. This inspires us that there is also a significant MLSE effect between the ruthenium and iridium with the alternate related ligand. Thus, we believe that introduction the active small molecule into ruthenium and iridium complexes might achieve the immune effect of Ru and Ir species, which would help to expand the repertoire of metal-based drugs as immune agonists. Our group successfully developed a Ru-arene complex CPI-Ru through an efficient CuAAC reaction with high cytotoxicity and selectivity towards CML(Chronic Myeloid Leukemia) cells and low toxicity against normal HLF cells(Human Fetal Lung Fibroblast, HLF). CPI-Ru could significantly reduce the expression of CD47 on the surface of cancer cells, achieving an efficient CD47 blockade to suppress the “self” signal. This combination of CPI-Ru-based chemo-therapy and CD47 blockade might help to develop new metal-based therapeutical agents for improved cancer chemo-immunotherapy [18]. This inspired us that the significant MLSE effect between Ru/Ir and small molecule ligands could also be used to treat leukemia while reducing toxicity to normal cells.

Leukemia, commonly referred to as blood cancer, is a malignant disorder of the hematopoietic system with a high mortality rate [[19], [20], [21]]. NB4 cells serves as a vital model for studying acute promyelocytic leukemia (APL) and its treatment. Chemotherapy for APL typically involves a combination of all-trans retinoic acid and arsenic trioxide, which have shown remarkable efficacy in inducing differentiation of NB4 cells and promoting apoptosis in leukemic cells. However, the significant toxicity and side effects continue to drive ongoing research into the relevant molecular pathways and the exploration of novel therapeutic strategies. In this work, we have designed two metal complexes through integrating Ru/Ir center with oleanolic acid (ole) for the leukemia treatment. Oleanolic acid, a pentacyclic triterpenoid commonly found in plants, can induce apoptosis via the mitochondrial pathway by modifying the expression levels of the pro- and anti-apoptotic Bcl-2 families, specifically decreasing expression of anti-apoptotic Bcl-2 and increasing expression of pro-apoptotic Bax [22,23]. Our results demonstrated that both ole-Ru and ole-Ir exhibited high cytotoxicity towards the cancer cells especially NB4 cells via the late apoptosis pathway. More importantly, both ole-Ru and ole-Ir showed lower toxicity to normal human lung fibroblast cells compared to cisplatin, indicating higher selectivity for cancer cells. Additionally, both ole-Ru and ole-Ir could disrupt the mitochondrial membrane potential and increase the Cytochrome c and Caspase 3/9 proteins. These findings validate that the potential of Ru/Ir-based complexes for the treatment of APL cell lines, and also proves the effectiveness of MLSE effect between Ru/Ir and active small molecules in leukemia therapy [[24], [25], [26], [27]].