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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. Show less

Abstract Morphological profiling is a valuable tool in phenotypic drug discovery. The advent of high-throughput automated imaging has enabled the capturing of a wide range of morphological features of cells or organisms in response to perturbations at the single-cell resolution. Concurrently, significant advances in machine learning and deep learning, especially in computer vision, have led to substantial improvements in analyzing large-scale high-content images at high throughput. These efforts have facilitated understanding of compound mechanism of action, drug repurposing, characterization of cell morphodynamics under perturbation, and ultimately contributing to the development of novel therapeutics. In this review, we provide a comprehensive overview of the recent advances in the field of morphological profiling. We summarize the image profiling analysis workflow, survey a broad spectrum of analysis strategies encompassing feature engineering– and deep learning–based approaches, and introduce publicly available benchmark datasets. We place a particular emphasis on the application of deep learning in this pipeline, covering cell segmentation, image representation learning, and multimodal learning. Additionally, we illuminate the application of morphological profiling in phenotypic drug discovery and highlight potential challenges and opportunities in this field. Show less

Title: Lysosome-targeted cyclometalated Ir(III) complexes as photosensitizers/photoredox catalysts for cancer therapy. Abstract: 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. Show less

INTRODUCTION: Pharmacokinetic parameters assessment is a critical aspect of drug discovery and development, yet challenges persist due to limited training data. Despite advancements in machine learning and in-silico predictions, scarcity of data hampers accurate prediction of drug candidates' pharmacokinetic properties. AREAS COVERED: The study highlights current developments in human pharmacokinetic prediction, talks about attempts to apply synthetic approaches for molecular design, and searches several databases, including Scopus, PubMed, Web of Science, and Google Scholar. The article stresses importance of rigorous analysis of machine learning model performance in assessing progress and explores molecular modeling (MM) techniques, descriptors, and mathematical approaches. Transitioning to clinical drug development, article highlights AI (Artificial Intelligence) based computer models optimizing trial design, patient selection, dosing strategies, and biomarker identification. In-silico models, including molecular interactomes and virtual patients, predict drug performance across diverse profiles, underlining the need to align model results with clinical studies for reliability. Specialized training for human specialists in navigating predictive models is deemed critical. Pharmacogenomics, integral to personalized medicine, utilizes predictive modeling to anticipate patient responses, contributing to more efficient healthcare system. Challenges in realizing potential of predictive modeling, including ethical considerations and data privacy concerns, are acknowledged. EXPERT OPINION: AI models are crucial in drug development, optimizing trials, patient selection, dosing, and biomarker identification and hold promise for streamlining clinical investigations. Show less

Title: Towards efficient Ir(III) anticancer photodynamic therapy agents by extending π-conjugation on N^N ligands. Abstract: In this work we disclose a new family of biscyclometallated Ir(III) complexes of the general formula [Ir(C^N)2(N^N)]Cl (IrL1-IrL5), where HC^N is 1-phenyl-β-carboline and N^N ligands (L1-L5) are different diimine ligands that differ from each other in the number of aromatic rings fused to the bipyridine scaffold. The photophysical properties of IrL1-IrL5 were thoroughly studied, and theoretical calculations were performed for a deeper comprehension of the respective variations along the series. All complexes exhibited high photostability under blue light irradiation. An increase in the number of aromatic rings led to a reduction in the HOMO-LUMO band gap causing a red-shift in the absorbance bands. Although all the complexes generated singlet oxygen (1O2) in aerated aqueous solutions through a photocatalytic process, IrL5 was by far the most efficient photosensitizer. Consequently, IrL5 was highly active in the photocatalytic oxidation of NADH. The formation of aggregates in DMSO at a high concentration (25 mM) was confirmed using different techniques, but was proved to be negligible in the concentration range of biological experiments. Moreover, ICP-MS studies proved that the cellular uptake of IrL2 and IrL3 is much better relative to that of IrL1, IrL4 and IrL5. The antiproliferative activity of IrL1-IrL5 was investigated in the dark and under blue light irradiation against different cancer cell lines. Complexes IrL1-IrL4 were found to be cytotoxic under dark conditions, while IrL5 turned out to be weakly cytotoxic. Despite the low cellular uptake of IrL5, this derivative exhibited a high increase of cytotoxicity upon blue light irradiation resulting in photocytotoxicity indexes (PI) up to 38. IrL1-IrL4 showed lower photocytotoxicity indexes ranging from 1.3 to 17.0. Haemolytic experiments corroborated the compatibility of our complexes with red blood cells. Confocal microscopy studies proved their accumulation in mitochondria, leading to mitochondrial membrane depolarization, and ruled out their localization in lysosomes. Overall, the mitochondria-targeted activity of IrL5, which inhibits considerably the viability of cancer cells upon blue light irradiation, allows us to outline this PS as a new alternative to traditional chemotherapeutic agents. Show less

Indexing articles by their publication type and study design is essential for efficient search and filtering of the biomedical literature, but is understudied compared to indexing by MeSH topical terms. In this study, we leveraged the human-curated publication types and study designs in PubMed to generate a dataset of more than 1.2M articles (titles and abstracts) and used state-of-the-art Transformer-based models for automatic tagging of publication types and study designs. Specifically, we trained PubMedBERT-based models using a multi-label classification approach, and explored undersampling, feature verbalization, and contrastive learning to improve model performance. Our results show that PubMedBERT provides a strong baseline for publication type and study design indexing; undersampling, feature verbalization, and unsupervised constrastive loss have a positive impact on performance, whereas supervised contrastive learning degrades the performance. We obtained the best overall performance with 80% undersampling and feature verbalization (0.632 macro-F1, 0.969 macro-AUC). The model outperformed previous models (MultiTagger) across all metrics and the performance difference was statistically significant (p < 0.001). Despite its stronger performance, the model still has room for improvement and future work could explore features based on full-text as well as model interpretability. We make our data and code available at https://github.com/ScienceNLP-Lab/MultiTagger-v2/tree/main/AMIA. Show less

The article highlights the cooperative impact of azoheteroarenes [abbt: 2,2'-azobis(benzothiazole), L1-L3; bmpd: (E)-1,2-bis(1-methyl-1H-pyrazole-3-yl) diazene, L4] and coligands [bpy: 2,2'-bipyridine; pap: 2-phenylazopyridine] in tuning radical (N-N^•-) versus nonradical (N═N⁰) states of L on selective Os^II-platforms in structurally/spectroscopically characterized monomeric [1]ClO₄-[6]ClO₄ and [1](ClO₄)₂-[2](ClO₄)₂/[7](ClO₄)₂-[8](ClO₄)₂, respectively. The preferred syn-configuration of L in the complexes prevented obtaining ligand bridged dimeric species. It revealed that {Os(bpy)₂} facilitated the stabilization of both nonradical ([1](ClO₄)₂-[2](ClO₄)₂) and radical ([1]ClO₄-[2]ClO₄) states of L1/L2, while it delivered exclusively the radical form for L3 in [3]ClO₄. In contrast, {Os(pap)₂} generated radical states of L1-L3 in [4]ClO₄-[6]ClO₄, respectively, without any alteration of the redox state of Os^II and azo (N═N⁰) function of the pap coligand. The neutral state of L4 was, however, ascertained in [7](ClO₄)₂ or [8](ClO₄)₂ irrespective of the nature of the metal fragment {Os(bpy)₂} or {Os(pap)₂}, respectively. Switching between radical and nonradical forms of L in the complexes as a function L and coligand could be addressed based on their relative FMO (frontier molecular orbital) energies. Multiple close redox steps of the complexes extended a competitive electron transfer scenario between the redox active components including metal/L/bpy/pap, leading to delicate electronic forms in each case. Show less

DNA crosslinking agents such as cisplatin and related platinum(II) analogs are effective drugs to treat solid tumors. However, these therapeutics can cause high toxicity in the body, and tumors can develop resistance to them. To develop less toxic and more effective DNA crosslinkers, medicinal chemists have focused on tuning the ligands in square planar platinum(II) complexes to modulate their bioavailability, targeted cell penetration, and DNA binding rates. Unfortunately, linking in vitro DNA binding capacity of DNA crosslinkers with their in vivo efficacy has proven challenging. Here we report an electrochemical biosensor strategy that allows the study of platinum(II)-DNA binding in real time. Our biosensors contain a purine-rich deoxynucleotide sequence, T6 (AG)10 , modified with a 5' hexylthiol linker for easy self-assembly onto gold electrodes. The 3' terminus is functionalized with the redox reporter methylene blue. Electron transfer from methylene blue to the sensor is a function of platinum(II) compound concentration and reaction time. Using these biosensors, we resolve DNA binding mechanisms including monovalent and bivalent binding, as well as base stacking. Our approach can measure DNA binding kinetics in buffers and in 50 % serum, offering a single-step, real-time approach to screen therapeutic compounds during drug development. Show less

As the most frequent and deadly type of cancer in women, breast cancer has a high propensity to spread to the brain, bones, lymph nodes, and lungs. The discovery of cisplatin marked the beginning of the development of anticancer metal-based medications, although the drug's severe side effects have limited its usage in clinical settings. The remarkable antimetastatic and anticancer activity of different ruthenium complexes such as NAMI-A, KP1019, KP1339, etc. reported in the 1980s has bolstered the discovery of ruthenium complexes with various types of ligands for anticancer applications. The review meticulously elucidates the cytotoxic and antimetastatic potential of reported ruthenium complexes against breast cancer cells. Notably, arene-based and cyclometalated ruthenium complexes emerge as standout candidates, showcasing remarkable potency with notably low IC50 values. These findings underscore the promising therapeutic avenues offered by ruthenium-based compounds, particularly in addressing the challenges posed by conventional treatments in refractory or aggressive breast cancer subtypes. Moreover, the review comprehensively integrates a spectrum of ruthenium complexes, spanning traditional metal complexes to nano-based formulations and light-activated variants, underscoring the versatility and adaptability of ruthenium chemistry in breast cancer therapy. Show less

The endoplasmic reticulum plays an important role in maintaining the protein homeostasis of cells as well as regulating Ca2+ storage. An increased load of unfolded proteins in the endoplasmic reticulum due to alterations in the cell's metabolic pathway leads to the activation of the unfolded protein response, also known as ER stress. ER stress plays a major role in maintaining the growth and survival of various cancer cells, but persistent ER stress can also lead to cell death and hence can be a therapeutic pathway in the treatment of cancer. In this review, we focus on different types of small molecules that impair different ER stress sensors, the protein degradation machinery, and chaperone proteins. We also review the metal complexes and other miscellaneous compounds inducing ER stress through multiple mechanisms. Finally, we discuss the challenges in this emerging area of research and the potential direction of research to overcome them towards next-generation ER-targeted cancer therapy. Show less

The copious metabolic acid production and -extrusion by cancer cells render poorly vascularized regions of solid tumors highly acidic. A growing list of proton - and bicarbonate transporters has been suggested to contribute to net acid extrusion from cancer cells, and/or been shown to be dysregulated and favor malignant development in various cancers. The great majority of these roles have been studied at the level of the cancer cells. However, recent advances in understanding of the cellular and physicochemical heterogeneity of solid tumors both enable and necessitate a reexamination of the regulation and roles of acid–base transporters in such malignancies. This review will briefly summarize the state-of-the-art, with a focus on the SLC9A and SLC4A families, for which most evidence is available. This is followed by a discussion of key concepts and open questions arising from recent insights and of the challenges that need to be tackled to address them. Finally, opportunities and challenges in therapeutic targeting of the acid–base transportome in cancers will be addressed. Show less

Reactive oxygen species are essential molecules that are generated and eliminated through complex balanced mechanisms. Increased reactive oxygen species levels have a role in tumour development, and targeting reactive oxygen species and their regulatory machineries is a promising therapeutic strategy. This Review discusses recent research developments in the field, their implications for cancer drug discovery, as well as emerging concepts and future perspectives. Show less

Novel complexes of form (NHC)Au(SCOR) (NHC = N‐heterocyclic carbene, SCOR− = thiocarboxylate ligand) were synthesised and characterised by spectroscopic techniques and X‐ray diffraction studies. The results of NMR and X‐ray studies indicated that thiocarboxylate ligands are comparable with NHCs in their electron donor ability. The complexes were stable at room temperature in the solid state but in solution underwent disproportionation reactions to form equilibria with [Au(NHC)2]+ and [Au(SCOR)2]−. In solution, the thiocarboxylate ligand in (NHC)Au(SCOR) underwent rapid exchange with other thiocarboxylate or thiolate ligands. The (NHC)Au(SCOR) complexes showed toxicity against cisplatin‐resistant ovarian cancer cells (OVCAR‐8), with IC50 < 10 μM, in the range exhibited by cationic [Au(NHC)2]+ complexes well‐known for their promising anticancer activity. Show less

Dysregulation of Fibroblast Growth Factor Receptors (FGFRs) signaling has been associated with breast cancer, yet employing FGFR-targeted delivery systems to improve the efficacy of cytotoxic agents is still sparsely exploited. Herein, we report four new bi-functional ruthenium-peptide conjugates (RuPCs) with FGFR-targeting and pH-dependent releasing abilities, envisioning the selective delivery of cytotoxic Ru complexes to FGFR(+)-breast cancer cells, and controlled activation at the acidic tumoral microenvironment. The antiproliferative potential of the RuPCs and free Ru complexes was evaluated in four breast cancer cell lines with different FGFR expression levels (SKBR-3, MDA-MB-134-VI, MCF-7, and MDA-MB-231) and in human dermal fibroblasts (HDF), at pH 6.8 and pH 7.4 aimed at mimicking the tumor microenvironment and normal tissues/bloodstream pHs, respectively. The RuPCs showed higher cytotoxicity in cells with higher level of FGFR expression at acidic pH. Additionally, RuPCs showed up to 6-fold higher activity in the FGFR(+) breast cancer lines compared to the normal cell line. The release profile of Ru complexes from RuPCs corroborates the antiproliferative effects observed. Remarkably, the cytotoxicity and releasing ability of RuPCs were shown to be strongly dependent on the conjugation of the peptide position in the Ru complex. Complementary molecular dynamic simulations and computational calculations were performed to help interpret these findings at the molecular level. In summary, we identified a lead bi-functional RuPC that holds strong potential as a FGFR-targeted chemotherapeutic agent. Show less

Title: Endocytic Uptake of Self-Assembled Iridium(III) Nanoaggregates for Holistic Treatment of Metastatic 3D Triple-Negative Breast Tumor Spheroids. Abstract: Triple-negative breast cancer (TNBC) presents a formidable challenge due to its aggressive behavior and limited array of treatment options available. This study focuses on employing nanoaggregate material of organometallic Ir(III) complexes for treating TNBC cell line MDA-MB-231. In this approach, Ir(III) complexes with enhanced cellular permeability are strategically designed and achieved through the incorporation of COOMe groups into their structure. The lead compound, IrL1, exhibits promiscuous nanoscale aggregation in RPMI cell culture media, characterized by a stable hydrodynamic effective diameter ranging from 190 to 202 nm over 48 h. With excellent photo-responsive contrast-enhanced cell imaging properties IrL1 exhibits an outstanding IC50, 48h value of 36.05± 0.03 nm when irradiated with 390 nm light in MDA-MB-231 (IC50, 48 h of Cisplatin is 5.29 µµ). In cell, investigation confirms that IrL1 nanoaggregates internalization via energy-dependent endocytosis undergo ferroptosis and ROS mediated cell death in MDA-MB-231 cells. Further, these in vivo studies using NOD-SCID mice confirmed that IrL1 exhibits a tendency to ablate tumors inoculated in mice models at therapeutically relevant doses. Thus, this comprehensive approach holds promise for expanding the repertoire of organometallic Ir(III) nanoaggregates with adaptable characteristics, thereby advancing their clinical utility of nanomedicine in the holistic treatment of metastatic 3D triple-negative breast tumor spheroids. Show less

Title: Biotin-Pt(IV)-Ru(II)-Boron-Dipyrromethene Prodrug as "Platin Bullet" for Targeted Chemo- and Photodynamic Therapy. Abstract: Using the principle of "Magic Bullet", a cisplatin-derived platinum(IV) prodrug heterobimetallic Pt(IV)-Ru(II) complex, cis,cis,trans-[Pt(NH3)2Cl2{Ru(tpy-BODIPY)(tpy-COO)}(biotin)]Cl2 (Pt-Ru-B, 2), having two axial ligands, namely, biotin as water-soluble B-vitamin for enhanced cellular uptake and a BODIPY-ruthenium(II) (Ru-B, 1) photosensitizer having N,N,N-donor tpy (4'-phenyl-2,2':6',2″-terpyridine) bonded to boron-dipyrromethene (BODIPY), is developed as a "Platin Bullet" for targeted photodynamic therapy (PDT). Pt-Ru-B exhibited intense absorption near 500 nm and emission near 513 nm (λex = 488 nm) in a 10% dimethyl sulfoxide-Dulbecco's phosphate-buffered saline medium (pH 7.2). The BODIPY complex on light activation generates singlet oxygen as the reactive oxygen species (ROS) giving a quantum yield (ΦΔ) of ∼0.64 from 1,3-diphenylisobenzofuran experiments. Pt-Ru-B exhibited preferential cellular uptake in cancer cells over noncancerous cells. The dichlorodihydrofluorescein diacetate assay confirmed the generation of cellular ROS. Confocal images revealed its mitochondrial internalization. Pt-Ru-B showed submicromolar photocytotoxicity in visible light (400-700 nm) in A549 and multidrug-resistant MDA-MB-231 cancer cells. It remained nontoxic in the dark and less toxic in nontumorigenic cells. Cellular apoptosis and alteration of the mitochondrial membrane potential were evidenced from the respective Annexin V-FITC/propidium iodide assay and JC-1 dye assay. A wound healing assay using A549 cells and Pt-Ru-B revealed inhibition of cancer cell migration, highlighting its potential as an antimetastatic agent. Show less

AbstractArtificial metallo‐nucleases (AMNs) are small molecule DNA cleavage agents, also known as DNA molecular scissors, and represent an important class of chemotherapeutic with high clinical potential. This review provides a primary level of exploration on the concepts key to this area including an introduction to DNA structure, function, recognition, along with damage and repair mechanisms. Building on this foundation, we describe hybrid molecules where AMNs are covalently attached to directing groups that provide molecular scissors with enhanced or sequence specific DNA damaging capabilities. As this research field continues to evolve, understanding the applications of AMNs along with synthetic conjugation strategies can provide the basis for future innovations, particularly for designing new artificial gene editing systems. Show less

Advances in high-throughput high-resolution mass spectrometry and the development of thermal proteome profiling approach (TPP) have made it possible to accelerate a drug target search. Since its introduction in 2014, TPP quickly became a method of choice in chemical proteomics for identifying drug-to-protein interactions on a proteome-wide scale and mapping the pathways of these interactions, thus further elucidating the unknown mechanisms of action of a drug under study. However, the current TPP implementations based on tandem mass spectrometry (MS/MS), associated with employing lengthy peptide separation protocols and expensive labeling techniques for sample multiplexing, limit the scaling of this approach for the ever growing variety of drug-to-proteomes. A variety of ultrafast proteomics methods have been developed in the last couple of years. Among them, DirectMS1 provides MS/MS-free quantitative proteome-wide analysis in 5-min time scale, thus opening the way for sample-hungry applications, such as TPP. In this work, we demonstrate the first implementation of the TPP approach using the ultrafast proteome-wide analysis based on DirectMS1. Using a drug topotecan, which is a known topoisomerase I (TOP1) inhibitor, the feasibility of the method for identifying drug targets at the whole proteome level was demonstrated for an ovarian cancer cell line. Graphical Abstract Show less

Abstract Ferroptosis is a new form of regulated cell death featuring iron‐dependent lipid peroxides accumulation to kill tumor cells. A growing body of evidence has shown the potential of ferroptosis‐based cancer therapy in eradicating refractory malignancies that are resistant to apoptosis‐based conventional therapies. In recent years, studies have reported a number of ferroptosis inducers that can increase the vulnerability of tumor cells to ferroptosis by regulating ferroptosis‐related signaling pathways. Encouraged by the rapid development of ferroptosis‐driven cancer therapies, interdisciplinary fields that combine ferroptosis, pharmaceutical chemistry, and nanotechnology are focused. First, the prerequisites and metabolic pathways for ferroptosis are briefly introduced. Then, in detail emerging ferroptosis inducers designed to boost ferroptosis‐induced tumor therapy, including metal complexes, metal‐based nanoparticles, and metal‐free nanoparticles are summarized. Subsequently, the application of synergistic strategies that combine ferroptosis with apoptosis and other regulated cell death for cancer therapy, with emphasis on the use of both cuproptosis and ferroptosis to induce redox dysregulation in tumor and intracellular bimetallic copper/iron metabolism disorders during tumor treatment is discussed. Finally, challenges associated with clinical translation and potential future directions for potentiating cancer ferroptosis therapies are highlighted. Show less

Three phosphorescent iridium(III) complexes consisting bis-diphosphine ligands were prepared and characterized by single-crystal XRD, CHN analysis, spectroscopic techniques, cyclic voltammetry, and DFT. The synthesized complexes were the three monomeric [Ir(ppy)₂(L₁)Cl] (1), [Ir(ppy)₂(L₂)]Cl (2) and [Ir(ppy)₂(L₃)]Cl (3) where L₁ = bis-(diphenylphosphino)methane (dppm), L₂ = bis-(diphenylphosphino)propane (dppp) and L₃ = bis-(diphenylphosphino)benzene (dppbe). Complexes 1-3 gave an absorption band between 240 to 380 nm in both CH₂Cl₂ and DMSO, which is assigned as a charge transfer transition based on theoretical calculation. They showed a blue-green emission at 460-520 nm in DMSO with an absolute quantum efficiency of 0.013-0.046 at room temperature. The selective photo-induced electron transfer (PET) by Fe³⁺ in DMSO, was studied to obey the Rehm-Weller principle. The 1:1 binding soichiometry between 1-3 and Fe³⁺ was established by Job's plot. The binding constants (K_a) were determined using the Benesi-Hildebrand plot. All the complexes are extremely more potent than cisplatin for in vitro antiproliferative activity towards the human breast cancer cells, HCC1937, MCF-7, and MDA-MB-231. The values of IC₅₀ were in the range of 0.077-0.485 μM, and 1 exhibited the most effective IC₅₀ against MDA-MB-231 cell line, the triple-negative breast cancer cell. Their lipophilicities (log P) were also examined to explain the penetration ability of the studied complexes towards cell barriers, and transport to the molecular target. Show less

Triple-negative breast cancer (TNBC) is the most aggressive type of breast cancer, which owned severe resistance to platinum-based anticancer agents. Herein, we report a new metal-arene complex, Ru-TPE-PPh₃, which can be synthesized in vitro and in living cells with copper catalyzed the cycloaddition reaction of Ru-azide and alkynyl (CuAAC). The complex Ru-TPE-PPh₃ exhibited superior inhibition of the proliferation of TNBC MDA-MB-231 cells with an IC₅₀ value of 4.0 μM. Ru-TPE-PPh₃ could induce the over production of reactive oxygen species (ROS) to initiate the oxidative stress, and further damage the mitochondria both functionally and morphologically, as loss of mitochondrial membrane potential (MMP) and cutting the supply of adenosine triphosphate (ATP), the disappearance of cristae structure. Moreover, the damaged mitochondria evoked the occurrence of mitophagy with the autophagic flux blockage and cell death. The complex Ru-TPE-PPh₃ also demonstrated excellent anti-proliferative activity in 3D MDA-MB-231 multicellular tumor spheroids (MCTSs), indicating the potential to inhibit solid tumors in living cells. This study not only provided a potent agent for the TNBC treatment, but also demonstrated the universality of the bioorthogonally catalyzed lethality (BCL) strategy through CuAAC reation. Show less

Certain cancer cells within solid tumors experience hypoxia, rendering them incapable of oxidative phosphorylation (OXPHOS). Despite this oxygen deficiency, these cells exhibit biochemical pathway activity that relies on NAD+. This mini-review scrutinizes the persistent, residual Complex I activity that oxidizes NADH in the absence of oxygen as the electron acceptor. The resulting NAD+ assumes a pivotal role in fueling the α-ketoglutarate dehydrogenase complex, a critical component in the oxidative decarboxylation branch of glutaminolysis - a hallmark oncometabolic pathway. The proposition is that through glutamine catabolism, high-energy phosphate intermediates are produced via substrate-level phosphorylation in the mitochondrial matrix substantiated by succinyl-CoA ligase, partially compensating for an OXPHOS deficiency. These insights provide a rationale for exploring Complex I inhibitors in cancer treatment, even when OXPHOS functionality is already compromised. Show less

Title: A Ru(II) complex-based COX-2 targeting type I photosensitizer evokes ferroptosis and apoptosis. Abstract: Photodynamic therapy (PDT) often faces challenges such as oxygen dependence and limited tumour specificity. We report a tumour-targeting photosensitizer (PS), RuCXB, which enhances uptake by cancer cells by targeting overexpressed cyclooxygenase-2 enzyme in tumours. RuCXB also reduces oxygen dependence via a type I PDT mechanism and achieves a strong therapeutic effect through the synergistic induction of ferroptosis and apoptosis. This work presents a reliable strategy for developing potent PSs with enhanced PDT efficacy, tumour selectivity, and diminished oxygen dependence. Show less

The synthesis of triazoles has attracted a lot of interest in the field of organic chemistry because of its versatile chemical characteristics and possible biological uses. This review offers an extensive overview of the different pathways used in the production of triazoles. A detailed analysis of recent research indicates that triazole compounds have a potential range of pharmacological activities, including the ability to inhibit enzymes, and have antibacterial, anticancer, and antifungal activities. The integration of computational and experimental methods provides a thorough understanding of the structure–activity connection, promoting sensible drug design and optimization. By including triazoles as essential components in drug discovery, researchers can further explore and innovate in the synthesis, biological assessment, and computational studies of triazoles as drugs, exploring the potential therapeutic significance of triazoles. Graphical abstract Show less

Flavonol-metal complexes can enhance the biological activity of flavonols. Inspired by the potential of ruthenium-based drugs in pharmaceutical applications, seven flavonol-Ru (II) complexes were synthesized to evaluate their biological activities. Among these compounds, compounds 8, 11, and 12 showed potent antioxidant activities. Compound 12 exhibited superior anti-inflammatory activity to natural quercetin, which served as a positive control. This study is the first to report the free radical scavenging abilities and antioxidant activity of flavonol-Ru (II) complexes. Furthermore, compound 12 demonstrated comparable efficacy to 5-FU against human non-small-cell lung cancer cells (A549). These results strongly support the potential of flavonol-Ru (II) agents. Show less