Current medicinal chemistry最新文献

Introduction: In the context of repurposing antimicrobial fluoroquinolones (FQs), we propose that their increased efficacy is attributable to the lipophilic properties of the newly developed FQs.

Methods: This study involved the synthesis of 21 lipophilic-acid chelating fluoroquinolones (FQs) and their subsequent screening approaches for selective antiproliferative, antioxidant, and anti-inflammatory activities.

Results: Notably, the reduced FQ series, specifically 14c, demonstrated radical scavenging activities for NO and DPPH that were comparable to the referencing agents. In contrast to the others, the reduced 10a, 10b, and 14b FQs exhibited significant antioxidant effects. Predominantly, MCF7, HT29, T47D, and SW480 were the best target cell lines for the new FQs to exhibit their antiproliferative activities. In fact, many FQ derivatives have revealed IC50 values below 10 µM, mainly with MCF7 and HT29cell lines. Among the three synthesized series (nitro, reduced, and triazolo), the compounds (10a-d and 14a-d) of the reduced series exhibited the highest activities (lowest IC50) against the strongest four cell lines. All reduced series of hexyl phenyl 14a, 14c, and 14d with para-halogens were stronger than their hexyl amine counterparts 10a, 10c, and 10d. The selectivity indices for the new FQs were either equipotent or more potent than the reference cisplatin.

Discussion: The remarkable effects of the reduced series 14a, 14b, 14c, 10a, 10c, and 10d stemmed from metal chelation within the C8-C7 ethylene diamine bridge. Furthermore, the spatial and steric constraints introduced by the N1 substituent ultimately influenced the chelation geometry. Complexation studies revealed that central iron chelation is the predominant intracellular mechanism, whereas zinc chelation is the primary mode of interaction with the zinc-dependent metalloenzyme Glo-I. Mechanistically, nitroFQs 9d, 13a, and 13d and their respective reduced FQs 14a and 14d were shown to exhibit unprecedentedly equipotent Glo-I enzymatic inhibition, matching the IC50 value of myricetin (3.5 µM). Appreciably significant GLo-I inhibition with IC50 values ranging from 24-52 µM was obtained for nitroFQs and their reduced FQs in the ascending order of 9c < 9b < 13b < 14b < 10b < 10c < 10d.

Conclusion: The mechanism of action of the FQs involved acidic functional groups and a C7-C8 ethylenediamine chelation bridge, with iron chelation being the predominant pathway.

Introduction: Lung cancer is a leading cause of cancer-related morbidity and mortality. The development and evaluation of effective treatment strategies for lung cancer are of high clinical importance. Everolimus (Eve) has been shown to upregulate the expression of phosphatases and inhibit the migration and proliferation of A549 cancer cells. The present study focuses on the synthesis of biodegradable bovine serum albumin (BSA) nanoparticles for the loading and delivery of Eve.

Methods: In the desolvation process, Eve molecules were kept in the BSA system. The physicochemical properties of the Eve drug containing BSA nanoparticles (Eve@BSA) have been exactly characterized. The loading and release assays of Eve were also studied at different glutaraldehyde percentages, times, and solvents.

Results: Field emission scanning electron microscopy (FE-SEM) analysis of BSA nanoparticles revealed a spherical morphology with an average size of 93.7 ± 3.7 nm. The results demonstrated that BSA nanoparticles are highly efficient carriers, achieving an Eve loading efficiency of approximately 54% at 4% glutaraldehyde. The release of Eve from the BSA nanoparticles was dependent on the solvent and duration of incubation. According to the MTT assay, Eve@BSA exhibited low cytotoxicity and high biocompatibility against L929 fibroblast cells. In contrast, the cytotoxicity of Eve@BSA against A549 cells (IC50 ≈ 47 μg/mL) was significantly higher than that of free Eve (IC50 ≈ 283 μg/m- L) after 48 hours.

Discussion: The synergistic effects of Eva@BSA nanoformulation due to functional groups-rich BSA seemed to improve in vitro antiproliferation efficacies compared with the single treatment of Eve.

Conclusion: The findings confirm the synergistic anticancer effect of Eve@BSA, indicating that this nanosystem may serve as a promising candidate for the treatment of lung cancer.

Introduction: The development and progression of non-small cell lung cancer (NSCLC) are intricately linked to immune cell activation, but its related signature has not been reported.

Methods: This study combines in silico and in vitro approaches. TCGA-NSCLC and Gene Expression Omnibus (GEO) datasets were utilized to develop and validate a prognostic signature based on cell activation genes. The signature's validity was assessed through the identification of genomic, transcriptomic, tumor microenvironment (TME), and single-cell infiltration characteristics. The function of the candidate gene RORA was verified using CCK8, apoptosis, colony formation, wound healing, and transwell assays. The detailed mechanism of RORA was investigated through ChIP-PCR, luciferase assays, Western blot, and ROS detection.

Results: The prognostic signature was constructed from TCGA-NSCLC datasets and validated in six independent datasets (GSE30219, GSE33072, GSE37745, GSE41271, GSE42127, GSE50081). The signature was associated with LRP1B and RYR2 mutations, NSCLC-related pathways, drug response, and immune cell infiltration. The candidate gene RORA significantly inhibits the proliferation and migration abilities of NSCLC cell lines (A549 and NCI-H1299). Furthermore, the transcription factor RORA promotes ZNF490 expression, which subsequently inhibits NUDFs expression and oxidative phosphorylation (oxphos).

Discussion: The signature highlighted its significance with genomic features that were frequently reported as prognostic indicators (LRP1B and RYR2 mutations, cancer-related infiltration and pathway infiltration), and putative treatment response (IC50 in the TCGA dataset). Its detailed mechanism of candidate gene RORA revealed its role in oxphos, highlighting the crosstalk between metabolism and immune activation.

Conclusion: The model is robust and effectively reflects NSCLC heterogeneity while predicting prognosis. RORA promotes the expression of ZNF490 to inhibit NUDFs and oxidative phosphorylation.

Background: Respiratory syncytial virus (RSV) causes more than 30 million cases of lower respiratory tract infections (LRTIs) and approximately 3 million hospitalizations globally each year. Although RSV is particularly dangerous for young children, older adults and individuals with underlying health conditions or weakened immune systems are also at risk. Rapid diagnosis of RSV infection is crucial to ensure timely treatment and prevent disease spread. While conventional diagnostic techniques exist, many are time-consuming, expensive, or labor-intensive. Biosensors have recently emerged as a promising alternative.

Methods: This review involved gathering original articles published in English from various databases, including PubMed, Scopus, Web of Science, and Embase, between August and October, 2024. Additionally, reference lists from these articles were examined in Google Scholar for further relevant sources. Out of 147 electronically searched citations, 15 articles met the inclusion criteria.

Results: Genosensors, particularly those employing Surface-Enhanced Raman Scattering (SERS) and electrochemical detection, demonstrated the most significant potential for RSV diagnosis. Biosensors are increasingly being applied for RSV detection due to their high sensitivity, accuracy, and rapid results. The most prevalent conventional techniques for RSV detection include immunofluorescence (IF), ELISA, cell culture, and RT-PCR (Real-time PCR). While molecular methods are fast and sensitive, they require advanced laboratory equipment and trained personnel. In contrast, biosensors offer a rapid, reliable, and cost-effective diagnostic approach.

Conclusion: Biosensors represent a significant advancement in RSV diagnostics, particularly in resource-limited settings. Enhancing biosensor technology could improve accessibility, speed, and accuracy in RSV detection, ultimately leading to better patient outcomes and reduced disease transmission.

Marine invertebrates exhibit a vast taxonomic diversity, encompassing multiple phyla ranging from Porifera (sponges) to Echinodermata. These organisms inhabit complex marine environments and have evolved a diverse array of unique bioactive substances with various pharmacological effects, including antibacterial, antiviral, antitumor, and anti-inflammatory properties. As a result, they have long served as a crucial source of active natural products. The application prospects of these natural products are expanding rapidly across various fields, including medicine, cosmetics, and biotechnology, offering new possibilities for human health and sustainable development. This review compiles information on 159 novel natural products derived from marine invertebrates, which were first discovered in 2024. These compounds, originating from a diverse range of marine invertebrates, encompass various chemical classes, including terpenoids, alkaloids, peptides, and other unique categories. This review places a strong emphasis on elucidating their origins, intricate chemical structures, and promising biological activities. By presenting the latest discoveries and advancements in the field, this comprehensive review aims to offer valuable references and novel insights for the research and development of innovative antibacterial, antitumor, and anti-inflammatory drugs.

Introduction: This study explores the evaluation of 2- or 4-methyl-9H-xanthen-9-one derivatives containing aminophenols or aromatic chiral/achiral aminoalkanols as potential blood vessel-sealing agents.

Methods: A series of xanthone derivatives were synthesized and evaluated through multiple bioassays, including hyaluronidase inhibition assays, antiplatelet activity via collagen-induced platelet aggregation, antioxidant potential using DPPH and FRAP assays, and vasodilatory responses in isolated rat aortic rings precontracted with phenylephrine.

Results: Among the obtained derivatives, compound 2 (2-hydroxy-N-((9-oxo-9H-xanthen-2-yl)methyl)-2-phenylethan-1-aminium chloride) demonstrated the highest hyaluronidase inhibition (19.09% at 100 μM/L), comparable to the reference compound quercetin (26.17% at 100 μM/L). Furthermore, compound 2 exhibited significant antiplatelet activity, reducing collagen-induced aggregation by 40.42% at 200 μM (p < 0.0001), similar to quercetin (40.38% at 200 μM), though weaker than acetylsalicylic acid (ASA, 71% in-hibition at 50 μM). Antioxidant studies using DPPH and FRAP assays indicated that compound 1 (4-hydroxy-N-((9-oxo-9H-xanthen-2-yl)methyl)benzenaminium chloride) surpassed vitamin C's antioxidant effect by 35%, while showing high ferric-reducing activity (91%). Additionally, compound 2 demonstrated a vasodilatory effect on rat aortic rings precontracted with phenylephrine, in contrast to quercetin, which enhanced vasoconstriction.

Discussion: Quercetin and α-mangostin were selected as reference compounds due to their well-established vasorelaxant mechanisms and structural similarities to the synthesized xanthone derivatives, providing a basis for comparison in evaluating vascular sealing potential and endothelial protective activity.

Conclusion: The study's findings suggest that 2-methylxanthone derivatives, particularly compound 2, hold potential as vascular sealing agents with additional antiplatelet and vasorelaxant properties. Compound 1, based on the present study, was chosen for further research due to its significant antioxidant properties. These results warrant further pharmacological evaluation for cardiovascular applications.

This review addresses the challenge of radioresistance in cervical cancer by exploring the role of ferroptosis in enhancing the efficacy of radiotherapy (RT). It emphasizes the radiosensitizing effect of β-sitosterol through modulation of the GPX4/ACSL4 axis. β-Sitosterol targets mitochondrial membranes, inhibits GPX4 activity, and activates ACSL4, promoting polyunsaturated fatty acid synthesis and thereby facilitating ferroptosis. Preclinical models demonstrate that β-sitosterol significantly improves RT sensitivity and increases tumor iron accumulation. The review further proposes a predictive framework based on ox-LDL levels and the ACSL4/GPX4 ratio for potential clinical application, alongside discussions on innovative delivery systems, ferroptosis-apoptosis interactions, microbiota-mediated metabolic effects, and AI-driven optimization of RT-- drug combinations. These insights contribute to advancing personalized radiotherapy strategies for cervical cancer.

Aim: This study aimed to investigate the causal associations between nine cathepsins (B, E, F, G, H, L2, O, S, Z) and breast carcinogenesis using Mendelian Randomization (MR) analysis, thereby addressing the current lack of systematic causal evidence beyond observational studies.

Methods: Genetic instruments for circulating cathepsin levels were obtained from the INTERVAL study, and summary statistics for breast cancer were derived from the TRICL consortium. Univariate MR with Inverse Variance Weighting (IVW) served as the primary analysis, supplemented by assessments of heterogeneity, pleiotropy, and outliers. Multivariable MR was performed to confirm independent associations, and reverse MR was used to explore potential feedback from breast cancer to cathepsin expression.

Results: Higher genetically predicted cathepsin E was causally associated with an increased risk of breast cancer, whereas cathepsins O and S were protective. No significant associations were observed for the other six cathepsins. Multivariable MR confirmed these associations as independent of one another. Reverse MR suggested that breast cancer liability downregulates cathepsin H but does not influence cathepsins E, O, or S.

Conclusion: This is the first MR study to provide causal evidence implicating cathepsin E as a risk factor and cathepsins O and S as protective factors in breast cancer. The findings highlight the novelty of identifying specific cathepsins with opposing effects, nominating cathepsin E as a candidate serum biomarker and cathepsins O and S as potential therapeutic targets. These results warrant validation in diverse, multi-ethnic cohorts and longitudinal studies.

Background: Spirooxindoles have been reported to be effective anticancer drug candidates by displaying promising pre-clinical results. Therefore, to find out a lead spirocyclic oxindole template, a series of spirooxindole derivatives bearing pyrrolizidine (14a-e) and N-methyl pyrrolidine (15a-e) were synthesized using an efficient multicomponent, one-pot, and stereoselective [3+2] cycloaddition reaction and evaluated in vitro against HT29 and HCT116 human colon cancer cell lines.

Methods: The pyrrolizidine and N-methyl pyrrolidine spirooxindole derivatives were synthesised in excellent regio- and stereoselectivity using previously optimized reaction conditions. They were evaluated in vitro against cell lines HT29 and HCT116. In silico ADME profiling, molecular docking, and dynamics simulation studies were performed to ascertain the probable mode of action of the lead derivative.

Results and discussion: The spirooxindoles were characterized using FTIR, ESI-MS, 1H and 13C NMR, purity was determined by RP-HPLC, and stereochemistry was confirmed by X-ray crystallography. Compound 14a produced the best anti-colon cancer activity with IC50 values of 62.66 and 9.55 μM against HT29 and HCT116 human colon cancer cell lines, respectively. The in silico studies revealed that MDM2 protein inhibition is a probable mode of anti-colon cancer activity, supported by the data obtained in the molecular docking and molecular dynamics study.

Conclusion: The described [3+2] cycloaddition reaction proved to be a highly efficient and catalyst- free reaction. The in vitro cell viability assays and in silico studies revealed that more spirooxindoles can be designed with a varied degree of substitution to target colon cancer.

Introduction: Limited studies have explored how ferroptosis and Epithelial- Mesenchymal Transition (EMT) jointly affect the prognosis of Esophageal Squamous Cell Carcinoma (ESCC). This study aimed to develop a clinical prognostic model based on the combined impact of ESCC.

Methods: Gene expression levels and clinical data of ESCC patients were obtained from the Gene Expression Omnibus (GEO) and the Cancer Genome Atlas (TCGA) database. Using Cox regression analysis and Least Absolute Shrinkage and Selection Operator (LASSO) regression analysis, we identified nine prognostic genes to build a predictive model. Immune cell infiltration was evaluated using CIBERSORT and single-sample Gene Set Enrichment Analysis methods. Finally, in vitro experiments were conducted to assess the oncogenic effects of ACSL3 and VIM.

Results: We developed a Ferroptosis-EMT Integrated Score (FEIS) based on nine key genes. High-FEIS patients had worse survival, increased immune infiltration, and higher expression of immune checkpoints. A nomogram was built for prognosis prediction, and in vitro studies confirmed the tumor-promoting roles of ACSL3 and VIM.

Discussion: The FEIS model robustly predicts ESCC prognosis by integrating ferroptosis and EMT, offering novel biomarkers for personalized immunotherapy, though further validation is warranted.

Conclusion: Our study introduced a novel prognostic tool that integrates ferroptosis and EMT-related biomarkers and offers valuable insights for developing personalized treatment strategies for ESCC patients.