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A new generation of backbone-functionalized NHC–gold( i ) complexes reveals ferroptosis through comprehensive mechanistic and biological investigation. Show less

Abstract Most clinically used chemotherapeutic agents act by inducing apoptosis. However, their clinical effectiveness is often limited by poor therapeutic efficacy and the rapid development of drug resistance. In contrast, oncosis, as an inflammatory form of cell death independent of adenosine triphosphate (ATP) and apoptotic pathways, exhibits unique advantages in overcoming tumor drug resistance and regulating anti‐tumor immune responses. Herein, we present the first iridium(III)‐based immunogenic oncosis inducers designed to concurrently induce oncosis and activate the cGAS–STING pathway, thereby bridging chemotherapy with immunotherapy. Through a bioisosteric design strategy, we identified benzoselenazole and benzothiazole derivatives as key pharmacophores for triggering oncosis. These iridium(III)‐based oncosis‐inducers rapidly disrupt mitochondrial architecture, induce oxidative stress, and promote Ca(II) release, which subsequently activate calpain and porimin to initiate oncosis in multidrug‐resistant cancer cells. Transcriptomic profiling further revealed their ability to regulate actin cytoskeleton organization, modulate ABC transporter activity, and affect glycolysis/gluconeogenesis. Notably, the metal complexes induce mitochondrial swelling and mt‐DNA damage, leading to robust activation of the cGAS–STING innate immune pathway and eliciting a strong anticancer immune response. Based on these multimodal mechanisms, the Ir(III)‐based immunogenic oncosis inducers were able to effectively kill drug‐resistant cancer cells and enhance the anticancer immune response in tumor mouse models. Show less

The precise design strategies that achieve structural optimization of both metallodrugs and self-reported metallodrug carriers can overcome the major limitations of metallodrug development. Herein, we structurally modified a conventional half-sandwich Ru(arene)(bipyridine) complex into a fluorogenic and esterase-responsive prodrug nanosystem via functionalizing the N,N'-bidentate bipyridine ligand with 10,12-pentacosadiynoic acid derivative, thereby designing an amphiphilic complex with the ability for coassembly. Prior to obtaining the nanoassembly, in an attempt to infer the benefits of functionalizing the ligand, a series of four organoruthenium complexes, including the amphiphilic complex, was prepared and characterized. The nanoassembly is found to release the Ru complex in the presence of porcine liver esterase concomitantly with a 4-fold increase in its fluorescence intensity. Such a stimuli-responsive behavior is exploited for real-time release monitoring of Ru complex and understanding its functionality to induce cell death in HeLa and THP-1 cancer cells. Compared to the free Ru complex, this nanosystem exhibits better cellular uptake and 100-fold higher cytotoxicity in HeLa cancer cells while being less toxic in noncancerous GM5756 cells. N-Acetylcysteine-induced GSH augmentation studies revealed that the nanoassembly exerts antiproliferative activity through oxidative stress. Toxicity analysis in zebrafish embryos confirmed the biocompatibility of the nanoformulations, suggesting a promising future in vivo studies. Show less

While various metal complexes demonstrate immunogenic cell death (ICD)-inducing properties, there is a lack of studies comparing ICD properties in structurally similar complexes with different metal centers. In this study, we synthesized four structurally similar Rh(I) and Ir(I) complexes with redox-active 1,2-bis(arylimino)acenaphthene (Ar-bian) ligands and assessed their anticancer and ICD-inducing properties. Analysis of damage-associated molecular patterns (DAMPs), ROS localization and dying cell populations highlighted the distinct roles of the metal center and the ligands. Specifically, only Rh(I) complexes induced the release of the three essential DAMPs and high levels of late apoptotic cells, while the Ir(I) complexes failed to trigger crucial “eat-me” signals. This work offers valuable insights into structure–activity relationships in metal complexes in the context of ICD. Show less

An integrated multimodal imaging workflow of cryogenic super-resolution fluorescence microscopy and soft X-ray tomography, Orbitrap secondary ion mass spectrometry, and inductively coupled plasma-mass spectrometry has revealed the unexpected targeting of a half-sandwich cyclopentadienyl Rh(III) phenylazopyridine anticancer complex to cellular lipid membranes and lipid droplets. The complex accumulates in plasma membranes with a surprisingly intense switch-on luminescence in living cancer cells, drives remodeling of lipid droplet architecture, and penetrates deeply into lipid-rich tissue environments. DFT modeling shows strong supramolecular interactions between the complex and glycerophosphorylcholine lipids. Show less

The first comprehensive study of a series of seven mesoionic tetrazolylidene gold(I) chloride complexes (1-7) featuring a range of alkyl and aryl substituents (Me, t-Bu, iPr, Ph, Tol, Dipp, Mes) is reported. Three synthetic pathways enabling access to scarcely explored abnormal 1,3-disubstituted tetrazolium ligand precursors (L₁-L₇) have been established. All complexes are characterized by NMR spectroscopy, mass spectrometry, and elemental analysis, confirming their composition and purity. Single-crystal X-ray crystallography of six gold(I) complexes (1-6) reveals nearly linear coordination (176.49(11)-179.0(2)°) at the gold(I) center and a distinct geometric arrangement across the series. NMR stability studies with model nucleophiles L-cysteine (Cys) and glutathione (GSH) support the structural findings, demonstrating rapid and complete reaction of complexes 1-7 with thiols, as confirmed by ¹H NMR and ESI-MS. The antiproliferative activity of the obtained complexes (1-7) and selected precursors (L₂, L₃, L₅, L₇) has been evaluated using MTT assays against human A2780 (ovarian) and A549 (lung) cancer cell lines, alongside noncancerous VERO E6 kidney cells for comparison. Most of the complexes display high selectivity indices (SI^A2780 = 63.2-86.7) and potent antiproliferative effects in the low submicromolar range against A2780, outperforming cisplatin and matching the activity of auranofin. Overall, the results presented here demonstrate the potential of gold(I) tetrazolylidene-based complexes for medicinal applications. Show less

Ferroptosis is a type of programmed cell death characterized by accumulation of free iron, reactive oxygen species generation and lipid peroxidation and is distinct from other types of regulated cell deaths such as apoptosis, necrosis and autophagy. Ferroptosis is distinct from other programmed cell deaths for its iron dependence and its significant role in tumor suppression. Therefore, harnessing ferroptosis may offer promising avenues for cancer therapy. In the present review, the different pathways that lead to ferroptosis, the genes and transcription factors involved in both iron and lipid metabolism, as well as the impact of small‑molecule alterations on the regulation of ferroptotic cell death, were discussed. Furthermore, the emergence of combination therapies with ferroptosis‑inducing molecules that overcome resistance to conventional chemotherapy, particularly in solid tumors, were highlighted. Show less

Abstract This article presents the synthesis and detailed structural investigation of a new palladium(II) heteroligand complex trans-[PdCl(CNXyl)2(C{CN(H)Xyl}2)]Cl, containing an acyclic diaminocarbene ligand and two isocyanide ligands. X-ray diffraction and NMR spectroscopy revealed that complex is stabilized both in the crystal and in solution by a system of N–H···Cl– hydrogen bonds formed between one chloride anion and two N–H groups of the diaminocarbene ligand (N–H···Cl–···H–N), with calculated energies of 3.8–5.4 kcal/mol. A Cambridge Structural Database search identified 22 other palladium(II) acyclic diaminocarbene complexes with similar N–H···X···H–N (X = Cl–, Br–, O=C<, O=S<, etc.) hydrogen-bonded systems. The complex demonstrated significant antiproliferative activity against the triple-negative breast cancer cell line MDA-MB-231, with an IC50 value of 5.55 ± 0.45 µM, which is four times higher than that of cisplatin. Show less

We report the facile synthesis of new gold(I) carbene complexes based on a mesoionic cobaltocenylidene metallocarbene via a fluorinative desilylation reaction. The carbene has been characterized by a variety of spectroscopic methods, revealing that it has the highest HEP value reported for a MIC so far, suggesting that the carbene is highly electron donating. The properties of the new class of metallo-mesoionic carbenes is further investigated, revealing also exceptionally low TEP values. Electrochemical studies also suggest the cobaltocenium moiety to be further reducible. In addition, the cell growth inhibitory effects of the new metallocarbene complexes were explored in cancer cells and bacteria. The combination of electrochemical activity, exceptional electron donating properties and their putative application in medicinal chemistry makes these new metallo-MICs a highly interesting new class of ligands. Show less

Colorectal cancer (CRC) remains a major global health challenge, in which chronic inflammation and redox dysregulation are key drivers of tumor progression. Here, we report a rationally designed family of NSAID-derived alkyne ligands coordinated to JohnPhos-gold(I) fragments, affording eight new alkynyl gold(I) derivatives. Complexes based on naproxen, ibuprofen, and salicylic acid derivatives display potent antiproliferative activity against Caco-2/TC7 colon cancer cells, outperforming oxaliplatin and being comparable to auranofin, while showing markedly reduced cytotoxicity in breast cancer lines and nonmalignant cells, thus indicating promising selectivity. Mechanistic studies revealed that the most active complex, [Au(L1)JP] (1), which contains a naproxen-derived alkyne, inhibits thioredoxin reductase (TrxR), triggers ROS overproduction, disrupts mitochondrial membrane potential, and induces G1-phase arrest while only marginally increasing apoptosis. This suggests the involvement of additional forms of cell death or cytostatic effects. Additionally, complex 1 selectively inhibits the enzyme cyclooxygenase-2 (COX-2) over COX-1 and reduces IL-8 expression without affecting PTGS2 transcription, highlighting a post-transcriptional anti-inflammatory action. These results support NSAID-derived alkynyl gold(I) complexes as promising multitarget agents for colorectal cancer intervention, combining disruption and COX-2 modulation. Show less

Fluorescein isothiocyanate-conjugated Annexin V in combination with propidium iodide (PI) labelling is a widely used flow cytometric assay for quantifying apoptotic and necrotic cells in anticancer studies. However, increasing evidence suggests that double-positive cells, or the Annexin V⁺/PI⁺ fraction, may represent not only late apoptosis but also different modalities of regulated cell death, including necroptosis, pyroptosis, ferroptosis, and cuproptosis. By collating findings from preclinical studies across different cancer cells, this review highlights the need for consensus in interpreting Annexin V⁺/PI⁺ populations. In the absence of molecular and/or microscopy data, this fraction is more appropriately classified as undergoing 'late-stage cell death'. In short, establishing standardised interpretive criteria is crucial to enhance understanding, facilitate cross-study comparability, and improve the translational relevance of anticancer research. Show less

Photodynamic therapy (PDT) is a promising strategy for head and neck squamous cell carcinoma (HNSCC), but the immune consequences of tumor cell death remain incompletely understood. We compared two ruthenium(II) polypyridine photosensitizers (PSs) in HNSCC models and found that both were potently phototoxic (nanomolar IC₅₀s), triggered diverse cell death pathways (including autophagy and ferroptosis), and promoted hallmark danger signals of immunogenic cell death (ICD). Strikingly, only one PS induced apoptosis and strong endoplasmic reticulum (ER) stress, yet paradoxically led to immune tolerance in vivo. Conversely, the PS that did not induce apoptotic cell death with milder stress responses resulted in a better antitumor immunity in vivo. These unexpected findings challenge the prevailing view that PDT-triggered apoptosis and ER stress are essential for ICD. Our study underscores the complexity of PDT-induced cell death balance and immunogenic signals and highlights the need to redefine ICD-inducing criteria for the rational design of next-generation PSs. Show less

Despite the widespread use of chemotherapeutic agents, their reliance on apoptosis often limits therapeutic efficacy and leads to drug resistance. To overcome these challenges, alternative cell death mechanisms such as cuproptosis have gained significant attention. While previous studies have primarily focused on incorporation of Cu into nanostructures, this work presents the first example of a molecular tripodal Cu(II) complex as a potent cuproptosis inducer. Herein, a series of tripodal Cu(II) complexes were chemically synthesized and biologically evaluated. The most promising compound demonstrated remarkable cytotoxicity in the low micromolar to nanomolar range. Mechanistic studies revealed that the compound catalytically produced hydroxyl radicals in the mitochondria of cancerous cells, causing protein oligomerization and the disruption of iron-sulfur cluster proteins, ultimately triggering cell death by cuproptosis. Contrary to traditional chemotherapeutic agents that cause reduction in tumor size, this compound induced the fragmentation of three-dimensional tumor spheroids. Show less

High-Grade Serous Ovarian Cancer (HGSOC) is the most common and lethal subtype of ovarian cancer, known for its high aggressiveness and extensive genomic alterations. Typically diagnosed at an advanced stage, HGSOC presents formidable challenges in drug therapy. The limited efficacy of standard treatments, development of chemoresistance, scarcity of targeted therapies, and significant tumor heterogeneity render this disease incurable with current treatment options, highlighting the urgent need for novel therapeutic approaches to improve patient outcomes. In this study we report a straightforward and stereoselective synthetic route to novel Pd(II)-vinyl and -butadienyl complexes bearing a wide range of monodentate and bidentate ligands. Most of the synthesized complexes exhibited good to excellent in vitro anticancer activity against ovarian cancer cells. Particularly promising is the water-soluble complex bearing two PTA (1,3,5-triaza-7-phosphaadamantane) ligands and the Pd(II)-butadienyl fragment. This compound combines excellent cytotoxicity towards cancer cells with substantial inactivity towards non-cancerous ones. This derivative was selected for further studies on ex vivo tumor organoids and in vivo mouse models, which demonstrate its remarkable efficacy with surprisingly low collateral toxicity even at high dosages. Moreover, this class of compounds appears to operate through a ferroptotic mechanism, thus representing the first such example for an organopalladium compound. Show less

Tumor metastasis, the spread of cancer cells from the primary site to distant organs, remains a formidable challenge in oncology. Central to this process is the involvement of subcellular organelles, which undergo significant functional and structural changes during metastasis. Targeting these specific organelles offers a promising avenue for enhanced drug delivery and metastasis therapeutic efficacy. This precision increases the potency and reduces potential off-target effects. Moreover, by understanding the role of each organelle in metastasis, treatments can be designed to disrupt the metastatic process at multiple stages, from cell migration to the establishment of secondary tumors. This review delves deeply into tumor metastasis processes and their connection with subcellular organelles. In order to target these organelles, biomembranes, cell-penetrating peptides, localization signal peptides, aptamers, specific small molecules, and various other strategies have been developed. In this review, we will elucidate targeting delivery strategies for each subcellular organelle and look forward to prospects in this domain. Show less

Abstract Ferroptosis, a novel form of regulated cell death induced by the excessive accumulation of lipid peroxidation products, plays a pivotal role in the suppression of tumorigenesis. Two prominent mitochondrial ferroptosis defense systems are glutathione peroxidase 4 (GPX4) and dihydroorotate dehydrogenase (DHODH), both of which are localized within the mitochondria. However, the existence of supplementary cellular defense mechanisms against mitochondrial ferroptosis remains unclear. Our findings unequivocally demonstrate that inactivation of mitochondrial respiratory chain complex I (MCI) induces lipid peroxidation and consequently invokes ferroptosis across GPX4 low-expression cancer cells. However, in GPX4 high expression cancer cells, the MCI inhibitor did not induce ferroptosis, but increased cell sensitivity to ferroptosis induced by the GPX4 inhibitor. Overexpression of the MCI alternative protein yeast NADH-ubiquinone reductase (NDI1) not only quells ferroptosis induced by MCI inhibitors but also confers cellular protection against ferroptosis inducers. Mechanically, MCI inhibitors actuate an elevation in the NADH level while concomitantly diminishing the CoQH2 level. The manifestation of MCI inhibitor-induced ferroptosis can be reversed by supplementation with mitochondrial-specific analogues of CoQH2. Notably, MCI operates in parallel with mitochondrial-localized GPX4 and DHODH to inhibit mitochondrial ferroptosis, but independently of cytosolically localized GPX4 or ferroptosis suppressor protein 1(FSP1). The MCI inhibitor IACS-010759, is endowed with the ability to induce ferroptosis while concurrently impeding tumor proliferation in vivo. Our results identified a ferroptosis defense mechanism mediated by MCI within the mitochondria and suggested a therapeutic strategy for targeting ferroptosis in cancer treatment. Show less

AbstractPhotoactivatable metal complexes offer the prospect of novel drugs with low side effects and new mechanisms of action to combat resistance to current therapy. We highlight recent progress in the design of platinum, ruthenium, iridium, gold and other transition metal complexes, especially for applications as anticancer and anti‐infective agents. In particular, understanding excited state chemistry related to identification of the bioactive species (excited state metallomics/pharmacophores) is important. Photoactivatable metallodrugs are classified here as photocatalysts, photorelease agents and ligand‐activated agents. Their activation wavelengths, cellular mechanisms of action, experimental and theoretical metallomics of excited states and photoproducts are discussed to explore new strategies for the design and investigation of photoactivatable metallodrugs. These photoactivatable metallodrugs have potential in clinical applications of Photodynamic Therapy (PDT), Photoactivated Chemotherapy (PACT) and Photothermal Therapy (PTT). Show less

Mitochondria are dynamic organelles that are essential for cellular energy generation, metabolic regulation, and signal transduction. Their structural complexity enables adaptive responses to diverse physiological demands. In cancer, mitochondria orchestrate multiple cellular processes critical to tumor development. Metabolic reprogramming enables cancer cells to exploit aerobic glycolysis, glutamine metabolism, and lipid alterations, supporting uncontrolled growth, survival, and treatment resistance. Genetic and epigenetic alterations in mitochondrial and nuclear DNA disrupt oxidative phosphorylation, tricarboxylic acid cycle dynamics, and redox homeostasis, driving oncogenic progression. Mitochondrial dysfunction in tumors is highly heterogeneous, influencing disease phenotypes and treatment responses across cancer types. Within the tumor microenvironment, mitochondria profoundly impact immune responses by modulating T-cell survival and function, macrophage polarization, NK cell cytotoxicity, and neutrophil activation. They also mediate stromal cell functions, particularly in cancer-associated fibroblasts and tumor endothelial cells. Although targeting mitochondrial function represents a promising therapeutic strategy, mitochondrial heterogeneity and adaptive resistance mechanisms complicate interventional approaches. Advances in mitochondrial genome editing, proteomics, and circulating mitochondrial DNA analysis have enhanced tumor diagnostic precision. This review synthesizes the developmental landscape of mitochondrial research in cancer, comprehensively summarizing mitochondrial structural dynamics, metabolic plasticity, signaling networks, and interactions with the tumor microenvironment. Finally, we discuss the translational challenges in developing effective mitochondria-based cancer interventions. Show less

Mitochondria are bilayer membrane organelles with basic metabolic activity. They are considered hubs for biosynthesis, bioenergy, and signaling functions, coordinating major biological pathways. Mitochondria are coupled to the oxidation of fatty acids and pyruvate through electron transport chains and have historically been considered the primary source of cellular energy. Recent studies have depicted that mitochondria are centers that promote inflammatory responses and play a crucial role in combating pathogenic infections. Moreover, mitochondria provide the basis for tumor synthesis metabolism, control redox and calcium homeostasis, participate in transcriptional regulation, and control cell death. Mitochondria are involved in all steps of tumorigenesis. This review discusses the relationship between mitochondria (including mitochondrial metabolism and mitophagy) and tumors, and the relationship between mtDNA and inflammation, as well as its clinical application in inflammatory diseases. More importantly, the application and targeted treatment strategies provide more opportunities for the development of new anticancer drugs. Show less

A comprehensive review of metal-based inducers of immunogenic cell death (ICD), their design strategies, molecular mechanisms to trigger ICD, subsequent protective antitumor immune responses, as well as validation approaches. Show less

PT-112 is a novel small molecule exhibiting promising clinical activity in patients with solid tumors. PT-112 kills malignant cells by inhibiting ribosome biogenesis while promoting the emission of immunostimulatory signals. Accordingly, PT-112 is an authentic immunogenic cell death (ICD) inducer and synergizes with immune checkpoint inhibitors in preclinical models of mammary and colorectal carcinoma. Moreover, PT-112 monotherapy has led to durable clinical responses, some of which persisting after treatment discontinuation. Mitochondrial outer membrane permeabilization (MOMP) regulates the cytotoxicity and immunogenicity of various anticancer agents. Here, we harnessed mouse mammary carcinoma TS/A cells to test whether genetic alterations affecting MOMP influence PT-112 activity. As previously demonstrated, PT-112 elicited robust antiproliferative and cytotoxic effects against TS/A cells, which were preceded by the ICD-associated exposure of calreticulin (CALR) on the cell surface, and accompanied by the release of HMGB1 in the culture supernatant. TS/A cells responding to PT-112 also exhibited eIF2α phosphorylation and cytosolic mtDNA accumulation, secreted type I IFN, and exposed MHC Class I molecules as well as the co-inhibitory ligand PD-L1 on their surface. Acute cytotoxicity and HMGB1 release caused by PT-112 in TS/A cells were influenced by MOMP competence. Conversely, PT-112 retained antiproliferative effects and its capacity to drive type I IFN secretion as well as CALR, MHC Class I and PD-L1 exposure on the cell surface irrespective of MOMP defects. These data indicate a partial involvement of MOMP in the mechanisms of action of PT-112, suggesting that PT-112 is active across various tumor types, including malignancies with MOMP defects. Show less

Necroptosis, a non-apoptotic mode of programmed cell death, is characterized by the disintegration of the plasma membrane, ultimately leading to cell perforation and rupture. Recent studies have disclosed the mechanism of necroptosis and its intimate link with nanomaterials. Nanomedicine represents a novel approach in the development of therapeutic agents utilizing nanomaterials to treat a range of cancers with high efficacy. This article provides an overview of the primary mechanism behind necroptosis, the current research progress in nanomaterials, their potential use in various diseases—notably cancer, safety precautions, and prospects. The goal is to aid in the development of nanomaterials for cancer treatment. Show less

The need for selective and efficient anticancer therapies drives the development of gold N-heterocyclic carbene (NHC) as efficient metallodrugs. Their stability, tunable electronics, and versatile steric features make NHCs ideal ligands, which, paired with an antiproliferating gold centre, form an exemplary metal complex for anticancer research. This review highlights the progress made in designing gold NHC complexes, emphasizing strategies to enhance cytotoxicity and selectivity towards cancer cells while minimizing toxicity to healthy tissues, emphasizing the crucial role of the NHC ligand. Furthermore, challenges concerning revealing the precise modes of action are discussed. Mechanistic pathways beyond the inhibition of thioredoxin reductase are highlighted. By underlining recent developments, this review aims to pave the way to a rational design of next-generation gold NHC complexes. Show less

Tetrazoles are nitrogen-rich heterocycles that have attracted interest because of their numerous applications in pharmaceutical and medicinal chemistry. Four nitrogen atoms and one carbon atom make up these five-membered rings, which have special physicochemical and electrical characteristics, including acidity, resonance stabilization, and aromaticity. This article highlights the structure, spectroscopic characteristics, and physical and chemical characteristics of tetrazoles. It also describes how overlapping mechanisms, such as DNA replication inhibition, protein synthesis disruption, and oxidative stress induction, as well as similar therapeutic targets, enable inhibitors to serve as both antibacterial and anticancer agents. Tetrazole moieties have been fused with a range of pharmacophores, such as indoles, pyrazoles, quinolines, and pyrimidines, yielding fused derivatives that display substantial inhibitory activity against bacterial, fungal, and cancer cell lines, with certain compounds exhibiting efficacy comparable to or exceeding that of established therapeutic agents. The rational design of more efficacious tetrazole-based therapies is facilitated by structure-activity relationship analysis, which further highlights significant functional groups and scaffolds that contribute to increasing activity. We investigate the relationship between microbial inhibition and anticancer efficacy, opening up new avenues for the creation of multifunctional therapeutic agents. We hope that this study will offer significant guidance and serve as a valued resource for medicinal and organic researchers working on drug development and discovery in multifunctional therapeutics. The review involves a thorough investigation of tetrazole in recent years. Show less

Mitochondrial outer membrane permeabilization (MOMP) refers to the increase in permeability of the mitochondrial outer membrane, allowing proteins, DNA, and other molecules to pass through the intermembrane space into the cytosol. As a crucial event in the induction of apoptosis, MOMP plays a significant role in regulating various forms of cell death, including apoptosis, ferroptosis, and pyroptosis. Importantly, MOMP is not a binary process of "all-or-nothing." Under sub-lethal stress stimuli, cells may experience a phenomenon referred to as minority MOMP (miMOMP), where only a subset of mitochondria undergo functional impairment, thereby disrupting the normal life cycle of the cell. This can lead to pathological and physiological changes such as tumor formation, cellular senescence, innate immune dysfunction, and chronic inflammation. This review focuses on the diversity of MOMP events to elucidate how varying degrees of MOMP under different stress conditions influence cell fate. Additionally, it summarizes the current research progress on novel antitumor therapeutic strategies targeting MOMP in clinical contexts. Show less

Abstract The development of multifunctional carriers for gene delivery is a critical challenge in modern therapeutics, particularly in the context of multi‐drug therapy (MDT). In this study, we report the synthesis and characterization of fluorinated guanidino‐polyamine conjugates based on low‐generation polyamidoamine (PAMAM) dendrimers and low molecular weight polyethyleneimine (PEI) polymers. These conjugates are designed to act as both efficient transfection agents and artificial ribonucleases, providing a dual‐function approach to gene therapy. The functionalization with fluorinated guanidino groups enhances DNA condensation, facilitates intracellular delivery, and enables tracking via 19 F MRI. Potentiometric and kinetic studies demonstrate their phosphodiesterase activity on a model compound, with PAMAM G4 derivatives exhibiting the highest catalytic efficiency. Biolayer interferometry and transfection experiments confirm mRNA cleavage activity, leading to reduced gene expression. Additionally, transfection studies with plasmid DNA (pDNA) indicate high gene delivery efficiency, surpassing conventional PEI‐based systems while maintaining low cytotoxicity. These findings suggest that the conjugates presented herein, and in particular those derived from low‐generation PAMAM dendrimers, can serve as promising multifunctional carriers for a combined diagnostic and MDT, offering a new strategy for synergistic gene delivery and RNA degradation. Show less

The direct and atom economic synthesis of azulenyl-substituted gold(i) carbene complexes, based on the modular template synthesis using gold(i) isonitrile complexes and amine nucleophiles, is presented. First, two azulenyl-substituted isonitriles as ligands were synthesized from a functionalizable azulene derivative, the latter stemming from a gold-catalyzed dimerization of internal alkynes. These azulene-bound gold(i) isonitrile complexes allow the smooth nucleophilic attack by both aliphatic and aromatic amines. The newly synthesized azulene-substituted gold(i) carbene complexes were evaluated for in vitro anticancer activity against multiple human cancer cell lines. Six lead compounds demonstrated potent and selective cytotoxicity, exceeding that of cisplatin by at least an order of magnitude in resistant and aggressive cancer models. Structure-activity relationship analysis revealed that specific ligand modifications, such as the position of the azulene moiety tethered to the carbene unit or nitrogen-bound ethyl or cyclic groups, are critical for enhancing the anticancer activity. Show less