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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

Proteins are of great significance in living organisms. However, understanding their functions encounters numerous challenges, such as insufficient integration of multimodal information, a large number of training parameters, limited flexibility of classification-based methods, and the lack of systematic evaluation metrics for protein question answering systems. To tackle these issues, we propose the Prot2Chat framework. Show less

AbstractWe report the development of an efficient and versatile synthetic protocol for the preparation of gold(I) and palladium(II) complexes bearing N‐heterocyclic carbene (NHC) thioglucosides and their azolium precursors. Gold(I) and Nolan‐type palladium(II)‐allyl complexes were synthesized under mild aerobic conditions using potassium carbonate as a base. Additionally, allyl palladate complexes were prepared via a straightforward solvent‐free method. In vitro assays on three ovarian cancer cell lines (OVCAR‐5, A2780, and its cisplatin‐resistant clone A2780cis) revealed interesting structure‐activity relationships (SARs). Gold(I) complexes with saturated NHC ligands showed enhanced activity, while Nolan‐type palladium(II)‐allyl complexes with unsaturated NHC ligands exhibited higher efficacy. Allyl palladates demonstrated similar activity regardless of whether the ligand was saturated or not. The most promising compounds display high selectivity for cancer cells, with cytotoxicity comparable to cisplatin on A2780 and OVCAR‐5 lines and superior activity against the A2780cis line. Notably, these compounds showed minimal toxicity towards non‐cancerous MRC‐5 cells. This selective anticancer activity is likely due to the presence of glucoside units, suggesting their role as targeting agents. TLDR: The most promising compounds display high selectivity for cancer cells, with cytotoxicity comparable to cisplatin on A2780 and OVCAR‐5 lines and superior activity against the A2780cis line. Show less

ChEMBL is a large-scale, open-access, FAIR database of bioactive molecules with drug-like properties. ChEMBL 35 contains 17,500 approved drugs, and drugs that are progressing through the clinical development pipeline. Drug curation has formed an integral part of the core offering of the ChEMBL database since its inception. The paper is a reference guide to present the principles of why the ChEMBL drug data has been curated in a particular manner so that data users can better understand the nature of the data. The drug data include information on: names, synonyms and trade names, chemical structure or biological sequence, data sources, indications, mechanisms, warnings and drug properties such as maximum phase of development, type of molecule, prodrug status and first approval. The integrated nature of the drug data within the context of a bioactivity resource enables the wide use of the data set in drug discovery, AI and machine learning. Show less

Drug discovery has seen dramatic change over the last 25 years. The vertically integrated large company model prevalent for more than 50 years has at least partly been replaced with a more distributed drug discovery enterprise that includes large numbers of small research organizations. Show less

Mitochondria are essential organelles for many aspects of cellular homeostasis. They play an indispensable role in the development and progression of diseases, particularly cancer which is a major cause of death worldwide. We analyzed the scientific research output on mitochondria and cancer via PubMed and Web of Science over the period 1990-2023. 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

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

Copper(II), manganese(II), and mercury(II) complexes of 4-amino-5-(2-(1-pyridine-2-yl)ethylidene)hydrazinyl)-4H-1,2,4-triazole-3-thiol (H2TAP) were synthesized and characterized using CHN analysis, FT-IR, 1H-NMR, 13C-NMR, UV–Vis, ESR, MS, PXRD, magnetic moment measurements, molar conductance, and TG/DTA. DFT calculations indicate octahedral geometries and the neutral bidentate or tridentate chelating behavior of the ligand. Cyclic voltammetry revealed the complexes’ redox properties, and Job’s method elucidated stoichiometric compositions in solution. Biochemical assays demonstrated antimicrobial activity against Escherichia coli, Staphylococcus aureus, and Candida albicans. The MnII complex exhibited potent antitumor activity against HepG-2 cells. Antioxidant and DNA binding studies showed promising results, with docking investigations indicating strong interactions between the ligand/complexes and target proteins (PDB: 1YWN) and DNA (PDB: 8EC1), suggesting therapeutic potential. Show less

Sassano et al. identify endoplasmic reticulum–mitochondria contact sites as the intracellular location where phospholipid peroxidation first occurs to promote ferroptosis. Manipulating these contact sites dictates ferroptosis sensitivity in breast cancer. Show less

Lipid peroxidation stands as a prominent hallmark and a prerequisite for the onset of ferroptosis. Lipid metabolism holds a pivotal role in regulating this process, forming the metabolic foundation for cellular sensitivity to ferroptosis. Studies in lipid metabolomics reveal that the activation of Polyunsaturated fatty acids (PUFA), specifically arachidonic acid and adrenoic acid (AdA), mediated by acyl-CoA synthetase long-chain family member 4 (ACSL4), represents a critical step in generating lipid peroxidation substrates. The expression level or enzymatic activity of ACSL4 emerges as a potential indicator of cellular susceptibility to ferroptosis. Additionally, other members of the ACSL family can indirectly influence the occurrence of ferroptosis by modifying the fatty acid composition of the cell membrane. Given the high expression of ACSL4 in various human tumors, targeting lipid peroxidation with ACSL4 as the focal point may pave a new path in tumor therapy. This article provides a brief overview of the primary structure and function of ACSL4, its role in lipid peroxidation, and summarizes the current advancements in drug development targeting ACSL4 and lipid peroxidation. Show less

Structure-based drug design is rapidly evolving, driven by advances in both physics-based and knowledge-based methods. These computational approaches are increasingly integrated across all stages of drug discovery. Despite remarkable progress, challenges remain in achieving accuracy, generalizability, computational efficiency, and chemical synthesizability. In this review, we provide a critical overview of advances, strengths, and limitations of recent methods. We also discuss synergies between the two concepts that hold promises for future advancements towards their practical applicability. Show less

Drug combination discovery remains slow and challenging. Here, the authors introduce Combocat, an open-source framework that combines acoustic liquid handling protocols with machine learning to achieve ultrahigh-throughput drug combination screening; as proof of concept, they use Combocat to screen 9,045 drug combinations in a neuroblastoma cell line. Show less

As two pivotal regulatory factors in cancer biology, oxidative stress and inflammation interact dynamically through complex network mechanisms to influence tumor initiation, progression, and treatment resistance. Oxidative stress induces genomic instability, oncogenic signaling activation, and tumor microenvironment (TME) remodeling via the abnormal accumulation of reactive oxygen species (ROS) or reactive nitrogen species (RNS). Conversely, inflammation sustains malignant phenotypes by releasing pro-inflammatory cytokines and chemokines and promoting immune cell infiltration. These processes create a vicious cycle via positive feedback loops whereby oxidative stress initiates inflammatory signaling, while the inflammatory milieu further amplifies ROS/RNS production, collectively promoting proliferation, migration, angiogenesis, drug resistance, and immune evasion in tumor cells. Moreover, their crosstalk modulates DNA damage repair, metabolic reprogramming, and drug efflux pump activity, significantly impacting the sensitivity of cancer cells to chemotherapy, radiotherapy, and targeted therapies. This review systematically discusses these advances and the molecular mechanisms underlying the interplay between oxidative stress and inflammation in cancer biology. It also explores their potential as diagnostic biomarkers and prognostic indicators and highlights novel therapeutic strategies targeting the oxidative stress-inflammation axis. The goal is to provide a theoretical framework and translational roadmap for developing synergistic anti-tumor therapies. Show less

Ubellacker and Dixon summarize the latest discoveries on ferroptosis in cancer, covering the molecular and cellular pathways underlying sensitivity and resistance to this type of cell death, as well as potential translational applications in cancer therapeutics. Show less