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The number of publications describing chemical structures has increased steadily over the last decades. However, the majority of published chemical information is currently not available in machine-readable form in public databases. It remains a challenge to automate the process of information extraction in a way that requires less manual intervention - especially the mining of chemical structure depictions. As an open-source platform that leverages recent advancements in deep learning, computer vision, and natural language processing, DECIMER.ai (Deep lEarning for Chemical IMagE Recognition) strives to automatically segment, classify, and translate chemical structure depictions from the printed literature. The segmentation and classification tools are the only openly available packages of their kind, and the optical chemical structure recognition (OCSR) core application yields outstanding performance on all benchmark datasets. The source code, the trained models and the datasets developed in this work have been published under permissive licences. An instance of the DECIMER web application is available at https://decimer.ai . Show less

Both ruthenium-containing complexes and 8-quinolinoline compounds have emerged as a potential novel agent for malignant tumor therapy. Here, three triphenylphosphine ruthenium complexes, [Ru(ZW1)(PPh₃)₂Cl₂] (PPh₃ = triphenylphosphine) (RuZ1), [Ru(ZW2)(PPh₃)₂Cl₂] (RuZ2) and [Ru(ZW2)₂(PPh₃)Cl₂]·CH₂Cl₂ (RuZ3) bearing 5,7-dichloro-8-quinolinol (H-ZW1) and 5,7-dichloro-8-hydroxyquinaldine (H-ZW2), have been synthesized, characterized and tested for their anticancer potential. We showed that triphenylphosphine ruthenium complexes RuZ1-RuZ3 impaired the cell viability of ovarian adenocarcinoma cisplatin-resistant SK-OV-3/DDP (SKO3CR) and SK-OV-3 (SKO3) cancer cells with greater selectivity and specificity than cisplatin. In addition, RuZ1-RuZ3 show higher excellent cytotoxicity than cisplatin towards SKO3CR cells, with IC₅₀ values of 9.66 ± 1.08, 4.05 ± 0.67 and 7.18 ± 0.40 μM, respectively, in which the SKO3CR cells was the most sensitive to RuZ1-RuZ3. Depending on the substituent type, the antiproliferative ability of RuZ1-RuZ3 followed the trend: -CH₃ > -H. However, RuZ1-RuZ3 have no obvious toxicity to normal cell HL-7702. Besides, RuZ1 and RuZ2 could induce mitophagy related-apoptosis pathways through suppression of mitochondrial membrane potential (ΔΨm), accumulation of [Ca²⁺] and reactive oxygen species (ROS), and regulation of LC3 II/LC3 I, Beclin-1, P62, FUNDC1, PINK1, Parkin, cleaved-caspase-3, caspase-9 and cytochrome c signaling pathway, and hindering the preparation of mitochondrial respiration complexes I and IV and ATP levels. Mechanistic study revealed that RuZ1 and RuZ2 induce apoptosis in SKO3CR cells via mitophagy related-apoptosis pathways induction and energy (ATP) generation disturbance. Taken together, the studied triphenylphosphine ruthenium complexes RuZ1-RuZ3 are promising chemotherapeutic agents with high effectiveness and low toxicity. Show less

Title: Cyclometalated iridium(III) complexes as anti-breast cancer and anti-metastasis agents via STAT3 inhibition. Abstract: Breast cancer is the most commonly diagnosed cancer and second‑leading cause of cancer deaths in women. Signal transducer and activator of transcription 3 (STAT3) plays a critical role in promoting breast cancer cell proliferation, invasion, angiogenesis, and metastasis, and the high expression of STAT3 is related to the occurrence and poor chemotherapy sensitivity of breast cancer. Iridium(III) complexes Ir-PTS-1- 4 containing a pterostilbene-derived ligand were synthesized to inhibit the STAT3 pathway in breast cancer. Ir-PTS-4 inhibited the proliferation of breast cancer cells by suppressing the expression of phosphorylated STAT3 and STAT3-related cyclin D1, arresting cell cycle in the S-phase, inducing DNA damage and reactive oxygen species (ROS) generation, eventually leading to autophagic cell death. The cell metastasis and invasion were also inhibited after Ir-PTS-4 treatment. Besides, Ir-PTS-4 exhibited excellent anti-proliferation activity in 3D multicellular tumor spheroids, showing potential for the treatment of solid tumors. This work presents the rational design of metal-based anticancer agents to block the STAT3 pathway for simultaneously inhibiting breast cancer proliferation and metastasis. Show less

Using resonance Raman spectroscopy and serial femtosecond X-ray crystallography, the authors show the heme a3 iron and CuB in the resting oxidized form of Cytochrome c Oxidase are coordinated by a hydroxide ion and a water molecule, respectively. Show less

Title: The ruthenium complex assists in nuclear targeting and selective killing of tumor cells. Abstract: In clinical studies, the toxicity of platinum-based antitumor drugs limits their use. DNA is the most widely studied target of metal-based complexes. Thus, nuclear targeting and selective killing have become the purpose of ruthenium complex design. We synthesized a carboline derivative and its ruthenium complex, NBD and NBD-Ru, and characterized their properties. UV spectra were used to monitor their stability. Transmission electron microscopy and dynamic light scattering were used to identify the self-assembly properties. Inductively coupled plasma mass spectrometry was used to assay the distribution of the Ru complexes in cells with or without transferrin. Besides, the tumor cell killing activities with or without transferrin were detected by MTT assay. An imaging flow cytometer was applied to observe the fluorescence further to identify the cellular distribution. The effects of NBD and NBD-Ru on DNA and the cell cycle were also measured. In vivo, the antitumor and antimetastatic activities of NBD and NBD-Ru were assessed in S180 and LLC tumor-bearing mice. We found that introducing Ru improved the solubility and stability, enabling NBD-Ru to self-assemble into nanoparticles with the EPR effect. At the same time, binding affinity with transferrin increased significantly after complexation, meaning NBD-Ru could target and selectively kill tumors via Tf/TfR pathway. More interestingly, ruthenium assisted the complex in achieving nuclear penetration, which can kill tumor cells by interacting with DNA. In vivo experiments further verified our conclusion in vitro. NBD-Ru could inhibit not only the growth of a primary tumor but also lung metastasis, which was related to the killing effect of the complex on tumor cells (Ki67) and inhibition of neovascularization (CD31). At the same time, the systemic toxicity of the ruthenium complex in vivo was reduced because of the targeting effect, and the biosafety was improved. In conclusion, we found that ruthenium assisted in nuclear targeting and selective killing in vitro and in vivo. Show less

Standard platinum-based chemotherapy is the basis of treatment of many cancers, however a proportion of patients do not derive benefit. Here the authors show that the platinum-based drug oxaliplatin accumulates in cancer-associated fibroblasts, activating pathways associated with cancer progression and resistance to therapy. Show less

Half-sandwich iridium(III) complexes show potential value in the anticancer field. However, complexes with favorable luminescence performance are rare, which limits further investigation of the anticancer mechanism. In this paper, 10 triphenylamine-modified fluorescent half-sandwich iridium(III) pyridine complexes {[(η⁵-Cp^x)Ir(L)Cl₂]} (Ir1-Ir10) were prepared and showed potential antiproliferative activity, effectively inhibiting the migration of A549 cells. Ir6, showing the best activity among these complexes, exhibited excellent fluorescence performance (absolute fluorescence quantum yield of 15.17%) in solution. Laser confocal detection showed that Ir6 followed an energy-dependent cellular uptake mechanism, specifically accumulating in mitochondria (Pearson co-localization coefficient of 0.95). A Western blot assay further confirmed the existence of a mitochondrial apoptotic channel. Additionally, Ir6 could arrest the cell cycle at the G₂/M phase, catalyze NADH oxidation, reduce the mitochondrial membrane potential, induce an increase in the level of intracellular reactive oxygen species, and exhibit a mechanism of oxidation. An in vivo antitumor assay confirmed that Ir6 can effectively inhibit tumor growth and is safer than cisplatin. Show less

To enhance the cytoselective behavior of the complexes, we intended to develop a CuAAC "click"-derived synthetic protocol for the preparation of 2-(2-(4-(4-(pyridin-2-yl)-1H-1,2,3-triazol-1-yl)butoxy)phenyl)benzo[d]thiazole-based Ru(II)/Ir(III)/Re(I) complexes, and their cytotoxicity against three different cancer cell lines (MCF-7, HeLa, and U87MG) in consort with one normal cell line (HEK-293) was evaluated. In our detailed investigations, the significant cytotoxic nature of the Ru(II) complex 7a compared to Ir(III) and Re(I) complexes (7b and 7c, respectively) was observed. Complex 7a was capable of MCF-7 cell apoptosis via the inhibition of both S- and G2/M-phase cell cycle arrest in association with a substantial quantity of ROS production and DNA intercalation. Show less

Although reactive aldehyde species (RASP) are associated with the pathogenesis of many major diseases, there are currently no clinically approved treatments for RASP overload. Conventional aldehyde detox agents are stoichiometric reactants that get consumed upon reacting with their biological targets, which limits their therapeutic efficiency. To achieve longer-lasting detoxification effects, small-molecule intracellular metal catalysts (SIMCats) were used to protect cells by converting RASP into non-toxic alcohols. It was shown that SIMCats were significantly more effective in lowering cell death from the treatment with 4-hydroxynon-2-enal than aldehyde scavengers over a 72 h period. Studies revealed that SIMCats reduced the aldehyde accumulation in cells exposed to the known RASP inducer arsenic trioxide. This work demonstrates that SIMCats offer unique benefits over stochiometric agents, potentially providing new ways to combat diseases with greater selectivity and efficiency than existing approaches. Show less

Abstract Patients with relapsed or refractory T-cell acute lymphoblastic leukemia (T-ALL) have a poor prognosis with few therapeutic options. With the goal of identifying novel therapeutic targets, we used data from the Dependency Map project to identify dihydroorotate dehydrogenase (DHODH) as one of the top metabolic dependencies in T-ALL. DHODH catalyzes the fourth step of de novo pyrimidine nucleotide synthesis. Small molecule inhibition of DHODH rapidly leads to the depletion of intracellular pyrimidine pools and forces cells to rely on extracellular salvage. In the absence of sufficient salvage, this intracellular nucleotide starvation results in the inhibition of DNA and RNA synthesis, cell cycle arrest, and, ultimately, death. T lymphoblasts appear to be specifically and exquisitely sensitive to nucleotide starvation after DHODH inhibition. We have confirmed this sensitivity in vitro and in vivo in 3 murine models of T-ALL. We identified that certain subsets of T-ALL seem to have an increased reliance on oxidative phosphorylation when treated with DHODH inhibitors. Through a series of metabolic assays, we show that leukemia cells, in the setting of nucleotide starvation, undergo changes in their mitochondrial membrane potential and may be more highly dependent on alternative fuel sources. The effect on normal T-cell development in young mice was also examined to show that DHODH inhibition does not permanently damage the developing thymus. These changes suggest a new metabolic vulnerability that may distinguish these cells from normal T cells and other normal hematopoietic cells and offer an exploitable therapeutic opportunity. The availability of clinical-grade DHODH inhibitors currently in human clinical trials suggests a potential for rapidly advancing this work into the clinic. Show less

Title: New ruthenium(II) complexes with cyclic thio- and semicarbazone: evaluation of cytotoxicity and effects on cell migration and apoptosis of lung cancer cells. Abstract: We describe the synthesis, physicochemical characterization, and in vitro antitumor assays of four novel analogous ruthenium(II) complexes with general formula cis-[RuII(N-L)(P-P)2]PF6, where P-P = bis(diphenylphosphine)methane (dppm, in complexes 1 and 2) or bis(diphenylphosphine)ethane (dppe, in complexes 3 and 4) and N-L = 5,6-diphenyl-4,5-dihydro-2H-[1,2,4]triazine-3-thione (Btsc, in complexes 1 and 3) or 5,6-diphenyltriazine-3-one (Bsc, in complexes 2 and 4). The data were consistent with cis arrangement of the biphosphine ligands. For the Btsc and Bsc ligands, the data pointed to monoanionic bidentate coordination to ruthenium(II) through N,S and N,O, respectively. Single-crystal X-ray diffraction showed that complex 1 crystallized in the monoclinic system, space group P21/c. Determination of the cytotoxicity profiles of complexes 1-4 gave SI values ranging from 1.19 to 3.50 against the human lung adenocarcinoma cell line A549 and the non-tumor lung cell line MRC-5. Although the molecular docking studies suggested that the interaction between DNA and complex 4 was energetically favorable, the experimental results showed that they interacted weakly. Overall, our results demonstrated that these novel ruthenium(II) complexes have interesting in vitro antitumor potential and this study may contribute to further studies in medicinal inorganic chemistry. Show less

Platinum-based drugs have revolutionized cancer chemotherapy; however, their therapeutic efficacy has been limited by severe side effects and drug resistance. Recently, approaches that target specific organelles in cancer cells have emerged as attractive alternatives to overcome these challenges. Many studies have validated these strategies and highlighted that organelle-targeted platinum complexes demonstrate increased anticancer activity, the ability to overcome drug resistance, novel molecular mechanisms, or even lower toxicity. This review provides a brief summary of various organelle-targeting strategies that promote the accumulation of platinum complexes in certain intracellular areas, such as the nucleus, mitochondria, endoplasmic reticulum (ER), and lysosomes. Moreover, the mechanisms through which these strategies improve anticancer performance, overcome drug resistance, and alter the action mode of conventional platinum drugs are discussed. By providing an extensive account of platinum complexes targeting different organelles, this review aims to assist researchers in understanding the design principles, identifying potential targets, and fostering innovative ideas for the development of platinum complexes. Show less

Title: Ruthenium(II) polypyridyl complexes with visible light-enhanced anticancer activity and multimodal cell imaging. Abstract: Ruthenium(II) polypyridyl complexes have drawn growing attention due to their photophysical properties and anticancer activity. Herein we report four ruthenium(II) polypyridyl complexes [(N^N)2RuII(L)]2+ (1-4, L = 4-anilinoquinazoline derivatives, N^N = bidentate ligands with bis-nitrogen donors) as multi-functional anticancer agents. The epidermal growth factor receptor (EGFR) is overexpressed in a broad range of cancer cells and related to many kinds of malignance. EGFR inhibitors, such as gefitinib and erlotinib, have been approved as clinical anticancer drugs. The EGFR-inhibiting 4-anilinoquinazoline ligands greatly enhanced the in vitro anticancer activity of these ruthenium(II) polypyridyl complexes against a series of human cancer cell lines compared to [Ru(bpy)2(phen)], but interestingly, these complexes were actually not potent EGFR inhibitors. Further mechanism studies revealed that upon irradiation with visible light, complexes 3 and 4 generated a high level of singlet oxygen (1O2), and their in vitro anticancer activities against human non-small-cell lung (A549), cervical (HeLa) and squamous (A431) cancer cells were significantly improved. Specifically, complex 3 displayed potent phototoxicity upon irradiation with blue light, of which the photo-toxicity indexes (PIs) against HeLa and A431 cells were 11 and 8.3, respectively. These complexes exhibited strong fluorescence emission at ca. 600 nm upon excitation at about 450 nm. A subcellular distribution study by fluorescence microscopy imaging and secondary ion mass spectrometry imaging (ToF-SIMS) demonstrated that complex 3 mainly localized at the cytoplasm and complex 4 mainly localized in the nuclei of cells. Competitive binding with ctDNA showed that complex 4 was more favorable to bind to the DNA minor groove than complex 3. These differences support that complex 3 possibly exerts its anticancer activities majorly by photo-induced 1O2 generation and complex 4 by binding to DNA. Show less

Cells tend to disintegrate themselves or are forced to undergo such destructive processes in critical circumstances. This complex cellular function necessitates various mechanisms and molecular pathways in order to be executed. The very nature of cell death is essentially important and vital for maintaining homeostasis, thus any type of disturbing occurrence might lead to different sorts of diseases and dysfunctions. Cell death has various modalities and yet, every now and then, a new type of this elegant procedure gets to be discovered. The diversity of cell death compels the need for a universal organizing system in order to facilitate further studies, therapeutic strategies and the invention of new methods of research. Considering all that, we attempted to review most of the known cell death mechanisms and sort them all into one arranging system that operates under a simple but subtle decision-making (If \ Else) order as a sorting algorithm, in which it decides to place and sort an input data (a type of cell death) into its proper set, then a subset and finally a group of cell death. By proposing this algorithm, the authors hope it may solve the problems regarding newer and/or undiscovered types of cell death and facilitate research and therapeutic applications of cell death. Show less

Hydrogen bonding is an interaction of great importance in drug discovery and development as it may significantly affect chemical and biological processes including the interaction of small molecules with other molecules, proteins, and membranes. In particular, hydrogen bonding can impact drug-like properties such as target affinity and oral availability which are critical to developing effective pharmaceuticals, and therefore, numerous methods for the calculation of properties such as hydrogen-bond strengths, free energy of hydration, or water solubility have been proposed over time. However, the accessibility to efficient methods for the predictions of such properties is still limited. Here, we present the development of Jazzy, an open-source tool for the prediction of hydrogen-bond strengths and free energies of hydration of small molecules. Jazzy also allows the visualisation of hydrogen-bond strengths with atomistic resolution to support the design of compounds with desired properties and the interpretation of existing data. The tool is described in its implementation, parameter fitting, and validation against two data sets of experimental hydration free energies. Jazzy is also applied against two chemical series of bioactive compounds to show that hydrogen-bond strengths can be used to understand their structure–activity relationships. Results from the validations highlight the strengths and limitations of Jazzy, and suggest its suitability for interactive design, screening, and machine-learning featurisation. Show less

The search for new metal-based photosensitizers (PSs) for anticancer photodynamic therapy (PDT) is a fast-developing field of research. Knowing that polymetallic complexes bear a high potential as PDT PSs, in this study, we aimed at combining the known photophysical properties of a rhenium(I) tricarbonyl complex and a ruthenium(II) polypyridyl complex to prepare a ruthenium-rhenium binuclear complex that could act as a PS for anticancer PDT. Herein, we present the synthesis and characterization of such a system and discuss its stability in aqueous solution. In addition, one of our complexes prepared, which localized in mitochondria, was found to have some degree of selectivity towards two types of cancerous cells: human lung carcinoma A549 and human colon colorectal adenocarcinoma HT29, with interesting photo-index (PI) values of 135.1 and 256.4, respectively, compared to noncancerous retinal pigment epithelium RPE1 cells (22.4). Show less

Title: Piano-stool ruthenium(II) complexes with maleimide and phosphine or phosphite ligands: synthesis and activity against normal and cancer cells. Abstract: In these studies, we designed and investigated cyto- and genotoxic potential of five ruthenium cyclopentadienyl complexes bearing different phosphine and phosphite ligands. All of the complexes were characterized with spectroscopic analysis (NMR, FT-IR, ESI-MS, UV-vis, fluorescence and XRD (for two compounds)). For biological studies, we used three types of cells - normal peripheral blood mononuclear (PBM) cells, leukemic HL-60 cells and doxorubicin-resistance HL-60 cells (HL-60/DR). We compared the results obtained with those obtained for the complex with maleimide ligand CpRu(CO)2(η1-N-maleimidato) 1, which we had previously reported. We observed that the complexes CpRu(CO)(PPh3)(η1-N-maleimidato) 2a and CpRu(CO)(P(OEt)3)(η1-N-maleimidato) 3a were the most cytotoxic for HL-60 cells and non-cytotoxic for normal PBM cells. However, complex 1 was more cytotoxic for HL-60 cells than complexes 2a and 3a (IC50 = 6.39 μM vs. IC50 = 21.48 μM and IC50 = 12.25 μM, respectively). The complex CpRu(CO)(P(OPh)3)(η1-N-maleimidato) 3b is the most cytotoxic for HL-60/DR cells (IC50 = 104.35 μM). We found the genotoxic potential of complexes 2a and 3a only in HL-60 cells. These complexes also induced apoptosis in HL-60 cells. Docking studies showed that complexes 2a and CpRu(CO)(P(Fu)3)(η1-N-maleimidato) 2b have a small ability to degrade DNA, but they may cause a defect in DNA damage repair mechanisms leading to cell death. This hypothesis is corroborated with the results obtained in the plasmid relaxation assay in which ruthenium complexes bearing phosphine and phosphite ligands induce DNA breaks. Show less

Title: Cyclometalated iridium(III) complexes induce immunogenic cell death in HepG2 cells via paraptosis. Abstract: Immunotherapy has been shown to provide superior antitumor efficacy by activating the innate immune system to recognize, attack and eliminate tumor cells without seriously harming normal cells. Herein, we designed and synthesized three new cyclometalated iridium(III) complexes (Ir1, Ir2, Ir3) then evaluated their antitumor activity. When co-incubated with HepG2 cells, the complex Ir1 localized in the lysosome, where it induced paraptosis and endoplasmic reticulum stress (ER stress). Notably, Ir1 also induced immunogenic cell death (ICD), promoted dendritic cell maturation that enhanced effector T cell chemotaxis to tumor tissues, down-regulated proportions of immunosuppressive regulatory T cells within tumor tissues and triggered activation of antitumor immunity throughout the body. To date, Ir1 is the first reported iridium(III) complex-based paraptosis inducer to successfully induce tumor cell ICD. Furthermore, Ir1 induced ICD of HepG2 cells without affecting cell cycle or reactive oxygen species levels. Show less

Triphenylphosphonium (TPP+) compounds like mito-metformin (MMe) target cancer cells by exploiting their hyperpolarized mitochondrial membrane potential. Here, we present a protocol for synthesizing TPP+ analogs with selectivity for mammalian cancer cells, reduced toxicity, and quantifiability using fluorine-19 nuclear magnetic resonance (19F-NMR). We describe steps for treating mammalian cells with mitochondria-targeted compounds, treating and preparing mouse tissue with these compounds, and 19F-NMR detection of MMe analogs in cells and tissue. TPP+-conjugated metformin analogs include para-methoxy (pMeO-MMe) and para-trifluoromethyl MMe (pCF3-MMe) and meta-trifluoromethyl MMe (mCF3-MMe). Show less

Title: Cyclometalated Ir(III) theranostic molecular probe enabled mitochondria targeted fluorescence-SERS-guided phototherapy in breast cancer cells. Abstract: The increased energy demands inherent in cancer cells necessitate a dependence on mitochondrial assistance for their proliferation and metastatic activity. Herein, an innovative photo-medical approach has been attempted, specifically targeting mitochondria, the cellular powerhouses, to attain therapeutic benefit. This strategy facilitates the rapid and precise initiation of apoptosis, the programmed cell death process. In this goal, we have synthesized cyclometalated Iridium (III) molecular probes, denoted as Ir-CN and Ir-H, with a nitrile (CN) and a hydrogen-functionalized bipyridine as ancillary ligands, respectively. Ir-CN has shown superior photosensitizing properties and lower dark cytotoxicity compared to Ir-H in the breast cancer cell line MCF-7, positioning it as the preferred probe for photodynamic therapy (PDT). The synthesized Ir-CN induces alterations in mitochondrial membrane potential, disrupting the respiratory chain function, and generating reactive oxygen species that activate signaling pathways leading to cell death. The CN-conjugated bipyridine ligand in Ir-CN contributes to the intense red fluorescence and the positive charge on the central metal atom facilitates specific mitochondrial colocalization (colocalization coefficient of 0.90). Together with this, the Iridium metal, with strong spin-orbit coupling, efficiently generates singlet oxygen with a quantum yield of 0.79. Consequently, the cytotoxic singlet oxygen produced by Ir-CN upon laser exposure disrupts mitochondrial processes, arresting the electron transport chain and energy production, ultimately leading to programmed cell death. This mitochondrial imbalance and apoptotic induction were dually confirmed through various apoptotic assays including Annexin V staining and by mapping the molecular level changes through surface-enhanced Raman spectroscopy (SERS). Therefore, cyclometalated Ir-CN emerges as a promising molecular probe for cancer theranostics, inducing laser-assisted mitochondrial damage, as tracked through bimodal fluorescence and SERS. Show less

Title: Mitochondria-targeted cyclometalated iridium (III) complexes: Dual induction of A549 cells apoptosis and autophagy. Abstract: In this study, we synthesized 4 cyclometalated iridium complexes using N-(1,10-phenanthrolin-5-yl)picolinamide (PPA) as the main ligand, denoted as [Ir(ppy)2PPA]PF6 (ppy = 2-phenylpyridine, Ir1), [Ir(bzq)2PPA]PF6 (bzq = benzo[h]quinoline, Ir2), [Ir(dfppy)2PPA]PF6 (dfppy = 2-(3,5-difluorophenyl)pyridine, Ir3), and [Ir(thpy)2PPA]PF6 (thpy = 2-(thiophene-2-yl)pyridine, Ir4). Compared to cisplatin and oxaliplatin, all four complexes exhibited significant anti-tumor activity. Among them, Ir2 demonstrated higher cytotoxicity against A549 cells, with an IC50 value of 1.6 ± 0.2 μM. The experimental results indicated that Ir2 primarily localized in the mitochondria, inducing a large amount of reactive oxygen species (ROS) generation, that decreased in mitochondrial membrane potential (MMP), reduced ATP production, and further impaired mitochondrial function, leading to cytochrome c release. Additionally, Ir2 caused cell cycle arrest at the S phase and induced apoptosis through the AKT-mediated signaling pathway. Further investigations revealed that Ir2 could simultaneously induce both apoptosis and autophagy in A549 cells, with the latter acting as a non-protective mechanism that promoted cell death. More importantly, Ir2 exhibited low toxicity to both normal LO2 cells in vitro and zebrafish embryos in vivo. Consequently, these newly developed Ir(III) complexes show great potential in the development of novel and low-toxicity anticancer agents. Show less

Based on bis-hetarylhydrazone H2L, a condensation product of 2,6-diacetylpyridine with 2-hydrazinobenzoxazole, a series of mononuclear copper(II) coordination compounds have been synthesized: [Cu(HL)NO3], [Cu(HL)(H2O)]ClO4, [Cu(HL)X] (X = Br−, X = Cl−). The structure of the compounds has been studied by means of NMR, IR, ESR, X-ray absorption spectroscopy and X-ray single crystal diffraction methods. In the compounds the copper center is in the square pyramidal environment. All compounds have been screened in vitro for their cytotoxic activity against HepG2 and MRC-5 cell lines. The ligand H2L shows no cytotoxicity at tested concentrations (1–100 μM), while all the Cu(II) complexes exhibit significant dose-dependent cytotoxic effects with IC50 values in the range of 1.4–3.0 μM (HepG2 cells). Show less

Title: Iridium(III) complexes inhibit the proliferation and migration of BEL-7402 cells through the PI3K/AKT/mTOR signaling pathway. Abstract: Iridium(III) complexes are largely studied as anti-cancer complexes due to their excellent anti-cancer activity. In this article, two new iridium(III) complexes [Ir(piq)2(THPIP)]PF6 (THPIP = 2,4-di-tert-butyl-6-(1H-imidazo[4,5-f][1,10]phenanthrolin-2-yl)phenol, piq = deprotonated 1-phenylisoquinoline) (Ir1) and [Ir(bzq)2(THPIP)]PF6 (bzq = deprotonated benzo[h]quinolone) (Ir2) were synthesized. 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assays showed that complex Ir1 exhibits moderate activity (IC50 = 29.9 ± 4.6 μM) and Ir2 shows high cytotoxicity (IC50 = 9.8 ± 1.8 μM) against BEL-7402 cells. Further studies on the mechanism showed that Ir1 and Ir2 induced apoptosis by changing the mitochondrial membrane potential, Ca2+ release, ROS accumulation, and cell cycle arrest at the S phase. The complexes can effectively inhibit cell colony formation and migration. The expression of B-cell lymphoma-2 (Bcl-2) family proteins, PI3K (phosphatidylinositol 3-kinase), AKT (protein kinase B), mTOR (mammalian target of rapamycin), and p-mTOR was studied by immunoblotting. Complexes Ir1 and Ir2 downregulated the expression of anti-apoptotic protein Bcl-2 and increased the expression of autophagy-related proteins of Beclin-1 and LC3-II. Further experiments showed that the complexes inhibited the production of glutathione (GSH) and increased the amounts of malondialdehyde (MDA). Fluorescence of HMGB1 was significantly increased. We also investigated the effect of the complexes on the expression of genes using RNA-sequence analysis, we further calculated the lowest binding energies between the complexes and proteins using molecular docking. Taken together, the above results indicated that complexes Ir1 and Ir2 induce apoptosis in BEL-7402 cells through a ROS-mediated mitochondrial dysfunction and inhibition of the PI3K/AKT/mTOR signaling pathway. Show less