Molecular Diversity最新文献

High concentrations of glutathione (GSH) in the tumor microenvironment (TME) represent a promising target for the development of polyurethane (PU)-based redox-responsive drug delivery systems. A series of 3-indolopyrazole acetamide derivatives were designed and synthesized in this study. The anti-proliferative activities of these compounds were evaluated in tumor cell lines, and the small molecule S11 (IC₅₀ = 2.64 μM) was identified as a potent inhibitor of human chronic myeloid leukemia K562 cells. To overcome the challenges of poor solubility and limited stability associated with the hydrophobic small molecule S11, polyurethane nanocapsules containing disulfide bonds (S-S) were innovatively synthesized. Subsequently, drug-loaded polyurethane nanocapsules (S11-1) were synthesized via interfacial polymerization. In vitro experimental results indicated that these nanocapsules exhibit enhanced drug release performance compared to free S11, with a GSH-responsive release mechanism. Furthermore, S11-1 effectively promotes K562 cell apoptosis, elevates intracellular Reactive Oxygen Species (ROS) levels, and induces mitochondrial membrane potential depolarization (MMP). Overall, S11-1 demonstrates considerable potential in enhancing drug delivery efficiency, improving targeting precision, and modulating biological activity.

A novel series of pyrazole-1,3,4-oxadiazole hybrids incorporating chalcone/oxime scaffolds (10a-10c, 11a-11c, 12a-12i, 13a-13i, and 14a-14i) was synthesized and subjected to an detailed cytotoxicity profile against the NCI-60 human cancer cell line panel. Several derivatives demonstrated broad-spectrum growth inhibition, with compounds 10b, 11a, and 11b emerging as the most active candidates, exhibiting mean GI₅₀ values in the low micromolar range (4.36-16.4 µM). A deeper biological assessment revealed that these hybrids act as dual inhibitors of EGFR and VEGFR-2, with compound 11b showing the highest potency (IC₅₀ = 26.38 nM and 114.17 nM, respectively). Mechanistic studies further confirmed that 11b induced G2/M phase arrest and triggered apoptotic pathways in MCF-7 cells. The oxime-containing analogs exhibited enhanced nitric oxide (NO) release, a property associated with modulation of angiogenesis and increased susceptibility of cancer cells to apoptosis, contributing to their observed anticancer activity. Molecular docking and structure-activity relationship analysis clarified the binding interactions and substitution patterns governing activity, and both cytotoxicity and mechanistic analyses converged on compound 11b as the most promising lead of the series.

Six series of ether (14a-i and 15a-i), ester (17a-f and 18a-f) and amine derivatives (21a and 22a-g) containing quinoxalinyl and quinolinyl moieties were synthesized and evaluated for their inhibitory activities against activin receptor-like kinase 5 (ALK5). Among all the compounds, compound 22f (IC₅₀ = 0.267 μM) exhibited the highest ALK5 inhibitory activity, comparable to that of the positive control LY-2157299. This study revealed that introducing amino groups into the side chains of quinoxalinyl and quinolinyl derivatives is more effective in enhancing ALK5 inhibition than ether or ester groups. These findings provide new insights and a theoretical foundation for the development of pyrazole-based ALK5 inhibitors.

Type 1 diabetes mellitus (T1DM) is a metabolic disease leading threat to human health around the world. Here we aimed to explore new biomarkers and potential therapeutic targets in T1DM through adopting integrated bioinformatics tools. The gene expression Omnibus (GEO) database was used to obtain next generation sequencing data (GSE270484) of T1DM and normal control samples. Furthermore, differentially expressed genes (DEGs) were screened using the DESeq2 package in R bioconductor package. Gene Ontology (GO) and pathway enrichment analyses were performed by g:Profiler. The protein-protein interaction (PPI) network was plotted with IID PPI database and visualized using Cytoscape. Module analysis of the PPI network was done using PEWCC. Then, microRNAs (miRNAs) and transcription factors (TFs) in T1DM were screened out from the miRNet and NetworkAnalyst database. Then, the miRNA-hub gene regulatory network and TF-hub gene regulatory network were constructed by Cytoscape software. Moreover, a drug-hub gene interaction network of the hub genes was constructed and predicted the drug molecule against hub genes. The receiver operating characteristic (ROC) curves were generated to predict diagnostic value of hub genes. Finally we performed molecular docking, ADMET profiling and molecular dynamics simulation studies of marine derived chemical constituents using Schrodinger Suite 2025-1. A total of 958 DEGs were screened: 479 up regulated genes and 479 down regulated genes. DEG were mainly enriched in the terms of developmental process, membrane, cation binding, response to stimulus, cell periphery, ion binding, neuronal system and metabolism. Based on the data of protein-protein interaction (PPI), the top 10 hub genes (5 up regulated and 5 down regulated) were ranked, including FN1, GSN, ADRB2, CEP128, FLNA, CD74, EFEMP2, POU6F2, P4HA2 and BCL6. The miRNA-hub gene regulatory network and TF-hub gene regulatory network showed that hsa-mir-657, hsa-miR-1266-5p, NOTCH1 and GTF3C2 might play an important role in the pathogenesis of T1DM. The drug-hub gene interaction network showed that Clenbuterol, Diethylstilbestrol, Selegiline and Isoflurophate predicted therapeutic drugs for the T1DM. Molecular docking and molecular dynamics simulation study revealed that CMNPD5805 and CMNPD30286 as potential inhibitors of FN1 (pdb id: 3M7P) a key biomarker in pathogenesis of T1DM. These findings promote the understanding of the molecular mechanism and clinically related molecular targets for T1DM.

Natural products represent a cornerstone in anticancer drug discovery owing to their structural diversity and unique bioactivities. Among them, matrine-a principal alkaloid derived from the traditional Chinese medicine Sophora flavescens-has attracted attention due to its documented antitumor properties; however, its clinical translation has been severely hampered by inherently low potency. To address this limitation, we designed and synthesized 28 novel matrine-thiophene hybrids via a structure-based molecular hybridization approach. Notably, the lead compound B10 exhibited a dramatic enhancement in anticancer efficacy, demonstrating IC₅₀ values of 4.13-5.79 µM against hepatocellular carcinoma (HCC) cell lines, which reflects an improvement of more than 1000-fold compared to the parent matrine, while showing minimal toxicity toward normal hepatocytes. Furthermore, in an in vivo xenograft model, B10 (40 mg/kg) achieved a tumor growth inhibition rate of 64.2%, outperforming the standard drug sorafenib. Critically, to decipher the underlying mechanism, we employed a proteolysis-targeting chimera (PROTAC) strategy, converting B10 into a targeted degrader, K2. This chemical probe enabled us to identify fibroblast growth factor receptor 3 (FGFR3) as a direct target of B10 and to elucidate its role in suppressing the FGFR3/PI3K/AKT signaling pathway. Collectively, this study not only presents B10 as a highly promising candidate for HCC treatment derived from a natural product scaffold, but also identifies FGFR3 as a novel therapeutic target in HCC, thereby providing an innovative and generalizable platform for target deconvolution and mechanistic investigation of natural product-based agents.