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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

In nature, life is inherently dissipative. Cells continuously consume energy (such as ATP) to sustain homeostasis, drive metabolism, and respond dynamically to environmental cues. Inspired by this principle, we develop a synthetic protocell system that exhibits dissipative behavior and initiates metabolic-like processes. Our design features synthetic vesicles formed from a cationic surfactant, which undergo a fuel-driven transformation into coacervate protocells via liquid-liquid phase separation. Dissipation is achieved through alkaline phosphatase (ALP)-catalyzed ATP hydrolysis, driving the reverse transition from coacervates back to vesicles. The distinct physicochemical properties and internal organization of vesicle and coacervate protocells enable us to design functional regulators capable of producing secondary signals, such as fluorescence and enzymatic products. This work offers a strategy for engineering enzymatic reaction-regulated dissipative behaviors of protocell systems that emulate key aspects of cellular metabolism, representing a step toward synthetic life-like systems with dynamic behavior and functional complexity. Show less

N-acetyl-l-cysteine (NAC) is a medication and a widely used antioxidant in cell death research. Despite its somewhat obscure mechanism of action, its role in inhibiting ferroptosis is gaining increasing recognition. In this study, we demonstrate that NAC treatment rapidly replenishes the intracellular cysteine pool, reinforcing its function as a prodrug for cysteine. Interestingly, its enantiomer, N-acetyl-d-cysteine (d-NAC), which cannot be converted into cysteine, also exhibits a strong anti-ferroptotic effect. We further clarify that NAC, d-NAC, and cysteine all act as direct reducing substrates for GPX4, counteracting lipid peroxidation. Consequently, only GPX4-rather than system xc-, glutathione biosynthesis, or ferroptosis suppressor protein 1-is necessary for NAC and d-NAC to prevent ferroptosis. Additionally, we identify a broad range of reducing substrates for GPX4 in vitro, including β-mercaptoethanol. These findings provide new insights into the mechanisms underlying the protective effects of NAC and other potential GPX4-reducing substrates against ferroptosis. 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

As the prominent feature of the development and progression of head and neck squamous cell carcinoma (HNSCC) is immunosuppression, therapeutic strategies to restore antitumor immunity have shown promising prospects. The efficacy of chemotherapy, a mainstay in HNSCC treatment, is exemplified by cytotoxic effects as well as immunostimulation, whereas compensatory activation of prosurvival signals in tumor tissues may compromise its efficacy. Aberrant activation of Src is present in many human malignancies including HNSCC, and is implicated in chemotherapy resistance. In this regard, tumor-microenvironment-responsive prodrug nanomicelles (PDO NPs) are rationally designed to combine chemotherapy (oxaliplatin, OXA) and Src inhibitors (dasatinib, DAS) for HNSCC therapy. PDO NPs are constructed by chemically modifying small-molecule prodrugs (DAS-OXA) loaded in block copolymer iPDPA with pH-triggered transforming capability. PDO NPs can controllably release drugs in response to tumor acidity, thus increasing tumor accumulation and therapeutic efficacy. Moreover, PDO NPs can elicit pyroptosis of tumor cells and induce T-cell-mediated antitumor immunity in murine HNSCC models. In summary, nanoprodrugs integrating Src inhibitors enhance the immunological effects of chemotherapy and provide insight into promising approaches for augmenting immunochemotherapy for HNSCC. STATEMENT OF SIGNIFICANCE: In this study, pH-responsive nanomicelles (PDO NPs) were constructed by loading a small molecular prodrug synthesized by the Src inhibitor dasatinib and the chemotherapy drug oxaliplatin into the amphiphilic block copolymer iPDPA to improve the immunological effects of chemotherapy for HNSCC. These nanomicelles can efficiently accumulate in tumor cells and achieve pH-responsive drug release. The PDO NPs can induce pyroptosis of tumor cells and potentiate antitumor immunity in subcutaneous and syngenetic orthotopic HNSCC mouse models, which may present a promising strategy to enhance immunochemotherapy for HNSCC. Show less

Dimethyl fumarate (DMF) is an antioxidative and anti-inflammatory drug approved for treatment of multiple sclerosis and psoriasis; however, beneficial effects of DMF have also been found in other inflammatory diseases and cancers. DMF is a prodrug that is immediately hydrolysed to monomethyl fumarate (MMF) in vivo. Both fumarates activate the nuclear factor (erythroid-derived 2)-like 2 (Nrf2) pathway, and Nrf2 is a key transcription factor of the antioxidant response. The immunosuppressive and anti-inflammatory actions of DMF occur through several mechanisms: via inhibition of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) pathway and by downregulation of aerobic glycolysis and pyroptosis in activated myeloid and lymphoid cells. MMF is also an agonist of hydroxycarboxylic acid receptor 2 (HCAR2). Differences in the strength of effects and mechanisms of action of both fumarates are discussed. The aim of this review was to analyse and compare the neuroprotective, antioxidative and anti-inflammatory effects of DMF and its active metabolite, MMF, in cellular (in vitro) and animal models of neurodegenerative diseases (NDs), other than multiple sclerosis. There are more than twenty studies that currently represent this field. Most of the studies are concerned with cellular or animal models of Alzheimer's disease (AD) and Parkinson's disease (PD), one utilized a mouse model of Huntington's disease (HD) and one clinical trial was carried out with amyotrophic lateral sclerosis (ALS) patients. The discrepancies in the results of the various studies are discussed, and issues requiring further research have been identified. Show less

The results of theoretical simulations of reaction paths for oxaliplatin from pro-drug into its active form responsible for cytostatic effect are presented. The studies based on the quantum-chemical density functional theory approach were performed considering environmental influence resulting from the aquation or electron donation. The hybrid mechanisms: hydrolytic mixed with electron driven were found to be the energetically favourable. Show less

AbstractAnticancer therapies, which can induce cell death and elevate antitumor immune response in the meantime, are considered as effective treatments for many types of cancers. Immunogenic cell death (ICD) induced by chemodrugs is a promising and typical strategy to achieve cell cytotoxicity and immunological enhancement together. However, due to the low level of ICD induction and less tumor‐targeting accumulation, application of traditional ICD inducers is limited. Here, tumor‐targeting core–shell magnetic nanoparticles (ETP‐PtFeNP:α‐enolase targeting peptide modified Pt‐prodrug loaded Fe3O4 nanoparticles) are developed to reinforce ICD induction of loaded‐oxaliplatin (IV) prodrug. After tumor‐targeting accumulation and endocytosis, platinum (IV) complexes are activated by intracellular reductive elimination to yield and release the Pt (II) congener, oxaliplatin, leading to DNA lesions and reactive oxygen species (ROS) generation. Simultaneously, in‐progress‐released ferric ions elicit highly toxic ROS (·OH or ·OOH) burst and interfere with the intracytoplasmic redox balance (like endoplasmic reticulum stress), leading to ICD‐associated immunogenicity enhancement and specific antitumor immune responses to kill the tumor cells synergistically. Meanwhile, the transverse relaxation rate R 2 of ETP‐PtFeNP is remarkably increased by more than three times while triggered by reductant, suggesting ETP‐PtFeNP a high‐sensitivity T 2 contrast agent for magnetic resonance imaging. Show less

Analysis of the origins of new drugs approved by the US Food and Drug Administration (FDA) from 1999 to 2008 suggested that phenotypic screening strategies had been more productive than target-based approaches in the discovery of first-in-class small-molecule drugs. However, given the relatively recent introduction of target-based approaches in the context of the long time frames of drug development, their full impact might not yet have become apparent. Here, we present an analysis of the origins of all 113 first-in-class drugs approved by the FDA from 1999 to 2013, which shows that the majority (78) were discovered through target-based approaches (45 small-molecule drugs and 33 biologics). In addition, of 33 drugs identified in the absence of a target hypothesis, 25 were found through a chemocentric approach in which compounds with known pharmacology served as the starting point, with only eight coming from what we define here as phenotypic screening: testing a large number of compounds in a target-agnostic assay that monitors phenotypic changes. We also discuss the implications for drug discovery strategies, including viewing phenotypic screening as a novel discipline rather than as a neoclassical approach. Show less