Current medicinal chemistry最新文献

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.

As a member of the TAM family of receptor kinases, the AXL protein plays an essential role in biological processes that maintain tissue homeostasis. Deregulated AXL signalling in tumour cells is linked to cancer progression, poor prognosis, metastasis, and reduced sensitivity to anti-cancer therapies. The underlying mechanisms are the activation of downstream signalling routes that promote cell survival, invasion and epithelial-mesenchymal transition. Two major AXL isoforms are expressed in human and rodent cells due to alternative splicing. Despite extensive research on AXL in cancer, little is known regarding the functional differences between these isoforms and whether they contribute to cancer differently. This review paper first outlines the structural and functional aspects of TAM biology with a particular focus on AXL. Next, we discuss the different levels of AXL regulation in tumour cells, including proteolytic cleavage, which leads to the formation of both extracellular and nuclear forms of AXL. Finally, we review articles investigating the variations in the function of AXL isoforms and report their associations with cancer. Notably, the formation of isoform 1 is likely to determine the presence of soluble AXL, elevated levels of which have been correlated with cancer progression in several tumour types. The review identifies areas deserving further investigation, such as how changes in isoform expression impact levels of soluble AXL in cancer. Additionally, isoform-specific downstream signalling effects and their impact on metastasis and drug resistance warrant more in-depth investigation.

Background: The growing threat of bacterial drug resistance compels researchers to pursue new therapeutic strategies. Finegoldia magna secretes SufA, a subtilisin- like protease that plays a critical role in virulence by degrading host defense molecules such as fibrinogen and LL-37. This study aimed to investigate the stereoselective inhibition of SufA by pure diastereoisomers of peptidyl 1-aminoalkylphosphonate diaryl esters and to evaluate their ability to reduce bacterial virulence and growth.

Methods: We synthesized and purified the diastereoisomers and assessed their ability to inhibit SufA using a fluorescent enzymatic assay. Antibacterial activity was evaluated against Gram-positive and Gram-negative bacteria. SDS-PAGE was used to examine the inhibition of SufA-mediated degradation of fibrinogen and LL-37. Molecular docking was performed, and binding was confirmed via Western blot.

Results: Diastereoisomer XIIIA inhibited SufA activity by 63% at 50 μM, protected fibrinogen and LL-37 from degradation, and significantly suppressed the growth of F. magna and E. coli. In contrast, XIIIB showed minimal activity. Molecular docking revealed key binding interactions between XIIIA and the SufA active site, which was further confirmed by Western blot analysis.

Discussion: These results demonstrate that stereochemistry critically influences SufA inhibition, with XIIIA showing superior potency and functional protection of host defense molecules. This supports its potential as an antivirulence agent. The validated probe also provides a tool for identifying serine protease targets in other pathogens.

Conclusion: Compound XIIIA exhibits potent stereoselective inhibition of SufA and notable antimicrobial effects, supporting its development as a novel therapeutic targeting bacterial virulence.

Background: An excessive inflammatory response plays a central role in the pathogenesis of ulcerative colitis (UC), but the specific cytokines involved remain unclear. This study aimed to identify inflammatory factors associated with UC and explore the possible mechanisms of the identified targets.

Methods: Protein quantitative trait loci (pQTLs) and expression quantitative trait loci (eQTLs) for inflammatory cytokines were obtained from a genome-wide pQTL study and the eQTL consortium, respectively. Summary data for UC from the exploration and validation cohorts were derived from a genome-wide association study and the Finngen cohort. MR and colocalization analyses were conducted to identify causal associations between inflammatory cytokines and UC. Bioinformatics analyses were employed to explore the involved biological processes of candidate targets. Immunohistochemistry was used to validate the expression of these candidate targets in colon tissues.

Results: Among all inflammatory cytokines, a significant causal association was identified between C-X-C motif chemokine ligand 5 (CXCL5) and UC. Using eQTL data, a significant genetic association was established between the mRNA expression of CXCL5 and its receptor, C-X-C motif chemokine receptor 2 (CXCR2), with UC. Colocalization analysis further supported these identified links. Differential expression analysis confirmed the dysregulation of the CXCL5/CXCR2 axis in UC patients. Enrichment and immune infiltration analysis indicated that the CXCL5/CXCR2 axis was involved in neutrophil chemotaxis and immune activation in UC. Moreover, CXCL5 expression was found to correlate with neutrophil extracellular trap (NET) formation in UC. Immunohistochemistry further confirmed the dysregulation of the CXCL5/CXCR2 axis in colon tissues of UC patients.

Discussion: The CXCL5/CXCR2 axis has been implicated to play a significant role within a broader inflammatory network that includes Interleukin (IL)-17, NF-κB, and Tumor Necrosis Factor (TNF) signaling pathways. Additionally, this axis interacts with macrophages and T cells, further contributing to the complexity of inflammatory responses in UC.

Conclusion: There is a significant association between CXCL5/CXCR2 and UC under the MR assumption, which is potentially linked with colonic chemotaxis and activation of neutrophils. These findings highlight the potential of CXCL5/CXCR2 as a therapeutic target for UC. However, future functional studies are needed to validate these findings and explore the exact mechanisms by which CXCL5/CXCR2 influences immune cell crosstalk in UC.