Confocal microscopic oxygen imaging of xenograft tumors using Ir(III) complexes as in vivo intravascular and intracellular probes.

Hypoxia is an important feature of the tumor microenvironment (TME) of most solid tumors, and it is closely linked to cancer cell proliferation, therapy resistance, and the tumor immune response. Herein, we describe a method for hypoxia-induced heterogeneous oxygen distribution in xenograft tumors based on phosphorescence imaging microscopy (PLIM) using intravascular and intracellular oxygen probes. We synthesized Ir(III) complexes with polyethylene glycol (PEG) units of different molecular weights into the ligand as intravascular oxygen probes, BTP-PEGm (m = 2000, 5000, 10000, 20000). BTP-PEGm showed red emission with relatively high emission quantum yield and high oxygen sensitivity in saline. Cellular and in vivo experiments using these complexes revealed that BTP-PEG10000 was the most suitable probe in terms of blood retention and ease of intravenous administration in mice. PLIM measurements of xenograft tumors in mice treated with BTP-PEG10000 allowed simultaneous imaging of the tumor microvasculature and quantification of oxygen partial pressures. From lifetime images using the red-emitting intracellular oxygen probe BTPDM1 and the green-emitting intravascular fluorescent probe FITC-dextran, we demonstrated hypoxic heterogeneity in the TME with a sparse vascular network and showed that the oxygen levels of tumor cells gradually decreased with vascular distance.

2-Phenylbenzothiazolyl iridium complexes as inhibitors and probes of amyloid ß aggregation.

The aggregation of amyloid ß (Aß) peptides is a significant hallmark of Alzheimer's disease (AD), and the detection of Aß aggregates and the inhibition of their formation are important for the diagnosis and treatment of AD, respectively. Herein, we report a series of benzothiazole-based Ir(III) complexes HN-1 to HN-8 that exhibit appreciable inhibition of Aß aggregation in vitro and in living cells. These Ir(III) complexes can induce a significant fluorescence increase when binding to Aß fibrils and Aß oligomers, while their measured log D values suggest these compounds could have enhanced blood-brain barrier (BBB) permeability. In vivo studies show that HN-1, HN-2, HN-3, and HN-8 successfully penetrate the BBB and stain the amyloid plaques in AD mouse brains after a 10-day treatment, suggesting that these Ir(III) complexes could act as lead compounds for AD therapeutic and diagnostic agent development.

Synthesis, photophysical characterisation, quantum-chemical study and in vitro antiproliferative activity of cyclometalated Ir(III) complexes based on 3,5-dimethyl-1-phenyl-1H-pyrazole and N,N-donor ligands.

In this paper, we present the synthesis of four new complexes: the dimeric precursor [Ir(dmppz)2(µ-Cl)]2 (1) (Hdmppz - 3,5-dimethyl-1-phenyl-1H-pyrazole) and heteroleptic bis-cyclometalated complexes: [Ir(dmppz)2(Py2CO)]PF6·½CH2Cl2 (2), [Ir(dmppz)2(H2biim)]PF6·H2O (3), and [Ir(dmppz)2(PyBIm)]PF6 (4), with auxiliary N,N-donor ligands: 2-di(pyridyl)ketone (Py2CO), 2,2'-biimidazole (H2biim) and 2-(2'-pyridyl)benzimidazole (PyBIm). In the obtained complexes, SC-X-ray analysis revealed that Ir(III) has an octahedral coordination sphere with chromophores of the type {IrN2C2Cl2} (1) or {IrN4C2} (2-4). The complexes obtained, which have been fully characterised by physicochemical methods (CHN, TG, FTIR, UV-Vis, PL and 1H, 13C, 15N NMR), were used to continue our studies on the factors influencing the cytotoxic properties of potential chemotherapeutic agents (in vitro). To this end, the following studies are presented: (i) comparative analysis of the effects on the biological properties of N,N-donor ligands and C,N-donor ligands in the studied complexes, (ii) studies of the interactions of the compounds with the selected molecular target: DNA and BSA (UV-Vis, CD and PL methods), (iii) and the reactivity towards redox molecules: GSH, NADH (UV-Vis and/or ESI-MS methods), (iv) cytotoxic activity (IC50) of potential chemotherapeutics against MCF-7, K-562 and CCRF-CEM cell lines.

Development of a NIR Iridium(III) Complex-Based Probe for the Selective Detection of Iron(II) Ions.

As a commonly used metal ion, iron(II) (Fe2+) ions pose a potential threat to ecosystems and human health. Therefore, it is particularly important to develop analytical techniques for the rapid and accurate detection of Fe2+ ions. However, the development of near-infrared (NIR) luminescence probes with good photostability for Fe2+ ions remain challenging. In this work, we report a novel iridium(III) complex-based luminescence probe for the sensitive and rapid detection of Fe2+ ions in a solution based on an Fe2+-mediated reduction reaction. This probe is capable of sensitively detecting Fe2+ ions with a limit of detection (LOD) of 0.26 µM. Furthermore, this probe shows high photostability, and its luminescence remains stable under 365 nm irradiation over a time period of 30 min. To our knowledge, this is first iridium(III) complex-based NIR probe for the detection of Fe2+ ions. We believe that this work provides a new method for the detection of Fe2+ ions and has great potential for future applications in water quality testing and human monitoring.

IrCytoToxDB: a dataset of iridium(III) complexes cytotoxicities against various cell lines.

Iridium(III) complexes nowadays became rising stars in various health-related applications. Thus, there is a necessity to assess cytotoxicity of the synthesized molecules against cancer/normal cell lines. In this report, we present a dataset of 2694 experimental cytotoxicity values of 803 iridium complexes against 127 different cell lines. We specify the experimental conditions and provide representation of the complexes molecules in machine-readable format. The dataset provides a starting point for exploration of new iridium-based cellular probes and opens new possibilities for predictions of toxicities and data-driven generation of new organometallic anticancer agents.

Lysosome-targeted cyclometalated Ir(III) complexes as photosensitizers/photoredox catalysts for cancer therapy.

A novel lysosome-targeted photosensitizer/photoredox catalyst based on cyclometalated Ir(III) complex IrL has been designed and synthesized, which exhibited excellent phosphorescence properties and the ability to generate single oxygen (1O2) and photocatalytically oxidize 1,4-dihydronicotinamide adenine dinucleotide (NADH) under light irradiation. Most importantly, the aforementioned activities are significantly enhanced due to protonation under acidic conditions, which makes them highly attractive in light-activated tumor therapy, especially for acidic lysosomes and tumor microenvironments. The photocytotoxicity of IrL and the mechanism of cell death have been investigated. Additionally, the tumor-killing ability of IrL under light irradiation was evaluated using a 4T1 tumor-bearing mouse model. This work provides a strategy for the development of lysosome-targeted photosensitizers/photoredox catalysts to overcome hypoxic tumors.

A pH ultra-sensitive hydrated iridium oxyhydroxide films electrochemical sensor for label-free detection of Vibrio parahaemolyticus.

Vibrio parahaemolyticus (V. parahaemolyticus) is a major foodborne pathogen, which can cause serious foodborne illnesses like diarrhoea. Rapid on-site detection of foodborne pathogens is an ideal way to respond to foodborne illnesses. Herein, we provide an electrochemical sensor for rapid on-site detection. This sensor utilized a pH-sensitive metal-oxide material for the concurrent isothermal amplification and label-free detection of nucleic acids. Based on a pH-sensitive hydrated iridium oxide oxyhydroxide film (HIROF), the electrode transforms the hydrogen ion compound generated during nucleic acid amplification into potential, so as to achieve a real-time detection. The results can be transmitted to a smartphone via Bluetooth. Moreover, HIROF was applied in nucleic acid device detection, with a super-Nernst sensitivity of 77.6 mV/pH in the pH range of 6.0-8.5, and the sensitivity showed the best results so far. Detection of V. parahaemolyticus by this novel method showed a detection limit of 1.0 × 103 CFU/mL, while the time consumption was only 30 min, outperforming real-time fluorescence loop-mediated isothermal amplification (LAMP). Therefore, the characteristics of compact, portable, and fast make the sensor more widely used in on-site detection.

Iridium-catalyzed diacylmethylation of tyrosine and its peptides with sulfoxonium ylides.

Pyridyloxy-directed Ir(III)-catalyzed diacylmethylation of protected tyrosines was achieved with alkyl and (hetero)aryl sulfoxonium ylides, furnishing tyrosine-based unnatural amino acids in good yields. Furthermore, the late stage exemplification of the strategy was successfully accomplished in tyrosine-containing dipeptides, tripeptides and tetrapeptides in moderate yields. This methodology is distinguished by its site-selectivity, tolerance of sensitive functional groups, scalability, and retention of the chiral configuration for tyrosine motifs.

Multifunctional chitosan-based hydrogels loaded with iridium nanoenzymes for skin wound repair.

Hemostasis, infection, oxidative stress, and inflammation still severely impede the wound repair process. It is significant to develop multifunctional wound dressings that can function as needed in various stages of wound healing. In this study, iridium nanoparticles (IrNPs) with multi-enzyme mimetic activity were complexed with chitosan (CS) and fucoidan (FD) for the first time to make a multifunctional CS/FD/IrNPs hydrogel with excellent antioxidant effect. The hydrogel has excellent physicochemical properties. In particular, the incorporation of IrNPs imparts excellent antioxidant properties to the hydrogel, which could scavenge reactive oxygen species (ROS). In addition, the hydrogel shows excellent hemostatic and antibacterial properties. The CS/FD/IrNPs hydrogel performs fast and efficient hemostasis in 21 s. Moreover, the blood loss of the CS/FD/IrNPs hydrogel group was approximately 10% of that in the control group and the antibacterial rate of CS/FD/IrNPs hydrogel against E. coli and S. aureus was up to 95 %. In vivo results demonstrate that CS/FD/IrNPs hydrogel promotes wound healing by attenuating ROS levels, reducing oxidative damage, mitigating inflammation, and accelerating angiogenesis. To summarize, the CS/FD/IrNPs hydrogel system, with hemostatic, antibacterial, antioxidant, anti-inflammatory and pro-healing activities, can be a promising and effective strategy for the treatment of clinically difficult-to-heal wounds.

Studies of Anticancer Activities In Vitro and In Vivo for Butyltin(IV)-Iridium(III) Imidazole-Phenanthroline Complexes with Aggregation-Induced Emission Properties.

Organotin(IV) and iridium(III) complexes have shown good application potential in the field of anticancer; however, the aggregation-caused quenching (ACQ) effect induced by high concentration or dose has limited the research on their targeting and anticancer mechanism. Then, a series of aggregation-induced emission (AIE)-activated butyltin(IV)-iridium(III) imidazole-phenanthroline complexes were prepared in this study. Complexes exhibited significant fluorescence improvement in the aggregated state because of the restricted intramolecular rotation (RIR), accompanied by an absolute fluorescence quantum yield of up to 29.2% (IrSn9). Complexes demonstrated potential in vitro antiproliferative and antimigration activity against A549 cells, following a lysosomal-mitochondrial apoptotic pathway. Nude mouse models further confirmed that complexes had favorable in vivo antitumor and antimigration activity in comparison to cisplatin. Therefore, butyltin(IV)-iridium(III) imidazole-phenanthroline complexes possess the potential as potential substitutes for platinum-based drugs.

A Nanoencapsulated Ir(III)-Phthalocyanine Conjugate as a Promising Photodynamic Therapy Anticancer Agent.

Despite the potential of photodynamic therapy (PDT) in cancer treatment, the development of efficient and photostable photosensitizing molecules that operate at long wavelengths of light has become a major hurdle. Here, we report for the first time an Ir(III)-phthalocyanine conjugate (Ir-ZnPc) as a novel photosensitizer for high-efficiency synergistic PDT treatment that takes advantage of the long-wavelength excitation and near infrared (NIR) emission of the phthalocyanine scaffold and the known photostability and high phototoxicity of cyclometalated Ir(III) complexes. In order to increase water solubility and cell membrane permeability, the conjugate and parent zinc phthalocyanine (ZnPc) were encapsulated in amphoteric redox-responsive polyurethane-polyurea hybrid nanocapsules (Ir-ZnPc-NCs and ZnPc-NCs, respectively). Photobiological evaluations revealed that the encapsulated Ir-ZnPc conjugate achieved high photocytotoxicity in both normoxic and hypoxic conditions under 630 nm light irradiation, which can be attributed to dual Type I and Type II reactive oxygen species (ROS) photogeneration. Interestingly, PDT treatments with Ir-ZnPc-NCs and ZnPc-NCs significantly inhibited the growth of three-dimensional (3D) multicellular tumor spheroids. Overall, the nanoencapsulation of Zn phthalocyanines conjugated to cyclometalated Ir(III) complexes provides a new strategy for obtaining photostable and biocompatible red-light-activated nano-PDT agents with efficient performance under challenging hypoxic environments, thus offering new therapeutic opportunities for cancer treatment.

Iridium(III) complexes as novel theranostic small molecules for medical diagnostics, precise imaging at a single cell level and targeted anticancer therapy.

Medical applications of iridium (III) complexes include their use as state-of-the-art theranostic agents - molecules that combine therapeutic and diagnostic functions into a single entity. These complexes offer a promising avenue in medical diagnostics, precision imaging at single-cell resolution and targeted anticancer therapy due to their unique properties. In this review we report a short summary of their application in medical diagnostics, imaging at single-cell level and targeted anticancer therapy. The exceptional photophysical properties of Iridium (III) complexes, including their brightness and photostability, make them excellent candidates for bioimaging. They can be used to image cellular processes and the microenvironment within single cells with unprecedented clarity, aiding in the understanding of disease mechanisms at the molecular level. Moreover the iridium (III) complexes can be designed to selectively target cancer cells,. Upon targeting, these complexes can act as photosensitizers for photodynamic therapy (PDT), generating reactive oxygen species (ROS) upon light activation to induce cell death. The integration of diagnostic and therapeutic capabilities in Iridium (III) complexes offers the potential for a holistic approach to cancer treatment, enabling not only the precise eradication of cancer cells but also the real-time monitoring of treatment efficacy and disease progression. This aligns with the goals of personalized medicine, offering hope for more effective and less invasive cancer treatment strategies.

Insights into the anticancer photodynamic activity of Ir(III) and Ru(II) polypyridyl complexes bearing ß-carboline ligands.

Ir(III) and Ru(II) polypyridyl complexes are promising photosensitizers (PSs) for photodynamic therapy (PDT) due to their outstanding photophysical properties. Herein, one series of cyclometallated Ir(III) complexes and two series of Ru(II) polypyridyl derivatives bearing three different thiazolyl-ß-carboline N^N' ligands have been synthesized, aiming to evaluate the impact of the different metal fragments ([Ir(C^N)2]+ or [Ru(N^N)2]2+) and N^N' ligands on the photophysical and biological properties. All the compounds exhibit remarkable photostability under blue-light irradiation and are emissive (605 < λem < 720 nm), with the Ru(II) derivatives displaying higher photoluminescence quantum yields and longer excited state lifetimes. The Ir PSs display pKa values between 5.9 and 7.9, whereas their Ru counterparts are less acidic (pKa > 9.3). The presence of the deprotonated form in the Ir-PSs favours the generation of reactive oxygen species (ROS) since, according to theoretical calculations, it features a low-lying ligand-centered triplet excited state (T1 = 3LC) with a long lifetime. All compounds have demonstrated anticancer activity. Ir(III) complexes 1-3 exhibit the highest cytotoxicity in dark conditions, comparable to cisplatin. Their activity is notably enhanced by blue-light irradiation, resulting in nanomolar IC50 values and phototoxicity indexes (PIs) between 70 and 201 in different cancer cell lines. The Ir(III) PSs are also activated by green (with PI between 16 and 19.2) and red light in the case of complex 3 (PI = 8.5). Their antitumor efficacy is confirmed by clonogenic assays and using spheroid models. The Ir(III) complexes rapidly enter cells, accumulating in mitochondria and lysosomes. Upon photoactivation, they generate ROS, leading to mitochondrial dysfunction and lysosomal damage and ultimately cell apoptosis. Additionally, they inhibit cancer cell migration, a crucial step in metastasis. In contrast, Ru(II) complex 6 exhibits moderate mitochondrial activity. Overall, Ir(III) complexes 1-3 show potential for selective light-controlled cancer treatment, providing an alternative mechanism to chemotherapy and the ability to inhibit lethal cancer cell dissemination.

Cyclometalated iridium(III) tetrazine complexes for mitochondria-targeted two-photon photodynamic therapy.

The fast-moving field of photodynamic therapy (PDT) has provided fresh opportunities to expand the potential of metallodrugs to combat cancers in a light-controlled manner. As such, in the present study, a series of cyclometalated Ir(III) complexes modified with a tetrazine functional group (namely, Ir-ppy-Tz, Ir-pbt-Tz, and Ir-dfppy-Tz) are developed as potential two-photon photodynamic anticancer agents. These complexes target mitochondria but exhibit low toxicity towards HLF primary lung fibroblast normal cells in the dark. When receiving a low-dose one- or two-photon PDT, they become highly potent towards A549 lung cancer cells (with IC50 values ranging from 24.0 nM to 96.0 nM) through the generation of reactive oxygen species (ROS) to induce mitochondrial damage and subsequent apoptosis. Our results indicated that the incorporation of tetrazine with cyclometalated Ir(III) matrices would increase the singlet oxygen (1O2) quantum yield (ΦΔ) and, meanwhile, enable a type I PDT mechanism. Ir-pbt-Tz, with the largest two-photon absorption (TPA) cross-section (σ2 = 102 GM), shows great promise in serving as a two-photon PDT agent for phototherapy.

Mitochondrial-targeted cyclometalated Ir(III)-5,7-dibromo/dichloro-2-methyl-8-hydroxyquinoline complexes and their anticancer efficacy evaluation in Hep-G2 cells.

Both 8-hydroxyquinoline compounds and iridium (Ir) complexes have emerged as potential novel agents for tumor therapy. In this study, we synthesized and characterized two new Ir(III) complexes, [Ir(L1)(bppy)2] (Br-Ir) and [Ir(L2)(bppy)2] (Cl-Ir), with 5,7-dibromo-2-methyl-8-hydroxyquinoline (HL-1) or 5,7-dichloro-2-methyl-8-hydroxyquinoline as the primary ligand. Complexes Br-Ir and Cl-Ir successfully inhibited antitumor activity in Hep-G2 cells. In addition, complexes Br-Ir and Cl-Ir were localized in the mitochondrial membrane and caused mitochondrial damage, autophagy, and cellular immunity in Hep-G2 cells. We tested the proteins related to mitochondrial and mitophagy by western blot analysis, which showed that they triggered mitophagy-mediated apoptotic cell death. Remarkably, complex Br-Ir showed high in vivo antitumor activity, and the tumor growth inhibition rate was 63.0% (P < 0.05). In summary, our study on complex Br-Ir revealed promising results in in vitro and in vivo antitumor activity assays.

Iridium(III) solvent complex-based electrogenerated chemiluminescence method for the detection of 3-methylhistidine in urine.

3-Methylhistidine (3-MeHis) is increasingly used as an indicator of muscle protein breakdown. The development of a sensitive, simple, and non-invasive method for 3-MeHis assay is important in clinical practice. Herein, a sensitive, simple, and non-invasive electrogenerated chemiluminescence (ECL) method was proposed for the quantitation of 3-MeHis in urine by using an iridium(III) solvent complex ([Ir(dfppy)2(DMSO)Cl], dfppy = 2-(2,4-difluorophenyl)pyridine, Ir-DMSO) as a signal reagent. The photoluminescence (PL) and ECL responses of Ir-DMSO to 3-MeHis were studied. The ECL intensity of Ir-DMSO was enhanced in the presence of 3-MeHis because of the coordination recognition between Ir-DMSO and the imidazole group of 3-MeHis. Based on the enhancement of ECL intensity, 3-MeHis can be sensitively detected in the range of 5 to 25 µM. The detection limit was 0.4 µM. This is the first report of an ECL method for the quantitation of 3-MeHis. Further, to investigate the feasibility of the Ir-DMSO-based ECL method in practical applications, the developed ECL method was applied for 3-MeHis assay in urine samples of 28 healthy volunteers and 2 patients. The urine samples from patients hospitalized with obesity and kidney disease and healthy individuals were distinguished by the ECL responses of Ir-DMSO. The proposed ECL method based on the coordination recognition between iridium(III) solvent complex and the imidazole group of 3-MeHis allows inexpensive, fast, non-invasive, and sensitive detection of 3-MeHis in urine, which is promising for assessing large volumes of patients for routine analysis in clinical practices.

Electrochemical oxidation of Florfenicol in aqueous solution with mixed metal oxide electrode: Operational factors, reaction by-products and toxicity evaluation.

Veterinary antibiotics have become an emerging pollutant in water and wastewater sources due to excess usage, toxicity and resistance to traditional water and wastewater treatment. The present study explored the degradation of a model antibiotic- Florfenicol (FF) using electrochemical oxidation (EO) with Ti-RuO2/IrO2 anode. The anode material was characterized using SEM-EDS studies expressing stable structure and optimal interaction of the neighboring metal oxides with each other. The EDS results showed the presence of Ru, Ir, Ti, O and C elements with 6.44%, 2.57%, 9.61%, 52.74% and 28.64% atomic weight percentages, respectively. Optimization studies revealed pH 5, 30 mA cm-2 current density and 0.05 M Na2SO4 for 5 mg L-1 FF achieved 90% TOC removal within 360 min treatment time. The degradation followed pseudo-first order kinetics. LC-Q-TOF-MS studies revealed six predominant byproducts illustrating hydroxylation, deflourination, and dechlorination to be the major degradation mechanisms during the electrochemical oxidation of FF. Ion chromatography studies revealed an increase in Cl-, F- and NO3- ions as treatment time progressed with Cl- decreasing after the initial phase of the treatment. Toxicity studies using Zebrafish (Danio rerio) embryo showed the treated sample to be toxic inducing developmental disorders such as pericardial edema, yolk sac edema, spinal curvature and tail malformation at 96 h post fertilization (hpf). Compared to control, delayed hatching and coagulation were observed in treated embryos. Overall, this study sets the stage for understanding the effect of mixed metal oxide (MMO) anodes on the degradation of veterinary antibiotic-polluted water and wastewater sources using electrochemical oxidation.

Mitochondria- and endoplasmic reticulum-localizing iridium(III) complexes induce immunogenic cell death of 143B cells.

Recent breakthroughs in cancer immunology have propelled immunotherapy to the forefront of cancer research as a promising treatment approach that harnesses the body's immune system to effectively identify and eliminate cancer cells. In this study, three novel cyclometalated Ir(III) complexes, Ir1, Ir2, and Ir3, were designed, synthesized, and assessed in vitro for cytotoxic activity against several tumor-derived cell lines. Among these, Ir1 exhibited the highest cytotoxic activity, with an IC50 value of 0.4 ± 0.1 µM showcasing its significant anticancer potential. Detailed mechanistic analysis revealed that co-incubation of Ir1 with 143B cells led to Ir1 accumulation within mitochondria and the endoplasmic reticulum (ER). Furthermore, Ir1 induced G0/G1 phase cell cycle arrest, while also diminishing mitochondrial membrane potential, disrupting mitochondrial function, and triggering ER stress. Intriguingly, in mice the Ir1-induced ER stress response disrupted calcium homeostasis to thereby trigger immunogenic cell death (ICD), which subsequently activated the host antitumor immune response while concurrently dampening the in vivo tumor-induced inflammatory response.

White light increases anticancer effectiveness of iridium(III) complexes toward lung cancer A549 cells.

Anticancer activity has been extensively studies. In this article, three ligands 2-(6-bromobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (BDIP), 2-(7-methoxybenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (MDIP), 2-(6-nitrobenzo[d][1,3]dioxol-5-yl)-1H-imidazo[4,5-f][1,10]phenanthroline (NDIP) and their iridium(III) complexes: [Ir(ppy)2(BDIP)](PF6) (ppy = deprotonated 2-phenylpyridine, 3a), [Ir(ppy)2(MDIP)](PF6) (3b) and [Ir(ppy)2(NDIP)](PF6) (3c) were synthesized. The cytotoxicity of 3a, 3b, 3c against Huh7, A549, BEL-7402, HepG2, HeLa, and non-cancer NIH3T3 was tested using 3-(4,5-dimethylthiazole-2-yl)-2,5-diphenyl tetrazolium bromide (MTT) method. The results obtained from the MTT test stated clearly that these complexes demonstrated moderate or non-cytotoxicity toward Huh7, BEL-7402, HepG2 and HeLa except A549 cells. To improve the anticancer efficacy, we used white light to irradiate the mixture of cells and complexes for 30 min, the anticancer activity of the complexes was greatly enhanced. Particularly, 3a and 3b exhibited heightened capability to inhibit A549 cells proliferation with IC50 (half maximal inhibitory concentration) values of 0.7 ± 0.3 µM and 1.8 ± 0.1 µM, respectively. Cellular uptake has shown that 3a and 3b can be accumulated in the cytoplasm. Wound healing and colony forming showed that 3a and 3b significantly hinder the cell migration and growth in the S phase. The complexes open mitochondrial permeability transition pore (MPTP) channel and cause the decrease of membrane potential, release of cytochrome C, activation of caspase 3, and finally lead to apoptosis. In addition, 3a and 3b cause autophagy, increase the lipid peroxidation and lead to ferroptosis. Also, 3a and 3b increase the expression of calreticulin (CRT), high mobility group box 1 (HMGB1), heat shock protein 70 (HSP70), thereby inducing immunogenic cell death.

Iminoamido chelated iridium(III) and ruthenium(II) anticancer complexes with mitochondria-targeting ability and potential to overcome cisplatin resistance.

A diverse set of neutral half-sandwich iminoamido iridium and ruthenium organometallic complexes is synthesized through the utilization of Schiff base pro-ligands with N˄N donors. Notably, these metal complexes with varying leaving groups (Cl- or OAc-) are formed by employing different quantities of the deprotonating agent NaOAc, and exhibit promising cytotoxicity against various cancer cell lines such as A549 and cisplatin-resistant A549/DDP lung cancer cells, as well as HeLa cells, with IC50 values spanning from 9.26 to 15.98 µM. Cytotoxicity and anticancer selectivity (SI: 1.9-2.4) of these metal complexes remain unaffected by variations in the metal center, leaving group, and ligand substitution. Further investigations reveal that these metal complexes specifically target mitochondria, leading to the depolarization of the mitochondrial membrane and instigating the production of intracellular reactive oxygen species. Furthermore, the metal complexes are found to induce late apoptosis and disrupt the cell cycle, leading to G2/M cell cycle arrest specifically in A549 cancer cells. In light of these findings, it is evident that the primary mechanism contributing to the anticancer effectiveness of these metal complexes is the redox pathway.