Chemical biology & drug design最新文献

Over the past two decades, the search for safe and effective COX-2 inhibitors has spurred extensive research on flavonoids. Within this context, synthetic flavonoid dimers have emerged as a promising subclass with potential anti-inflammatory activity. To investigate whether dimerization enhances their potency and selectivity, novel A-fused bis-chalcones and A-fused bis-flavones were synthesized and evaluated for their inhibitory activity against isolated human COX-1 and COX-2 enzymes, as well as their effects on prostaglandin E₂ production in whole human blood. Interestingly, the most active compound identified was a monomeric chalcone sharing the same substitution pattern as the top-performing bis-chalcone, suggesting that key structural features drive activity regardless of dimerization. While the dimeric nature of bis-chalcones did not enhance COX-2 inhibition or selectivity in this study, these results provide valuable insights into structure-activity relationships. Furthermore, all active compounds against the isolated enzyme showed reduced potency in whole blood, possibly due to plasma protein binding limiting bioavailability. This study highlights the importance of rational design for further development of dimeric flavonoids, in particular strategies aimed at optimizing bioavailability.

In this study, novel triazole derivatives were designed and synthesized for potential breast cancer treatment. A series of 1,2,4-triazole compounds bearing a 2,4-difluorophenyl moiety (3a-3r) was obtained through a two-step organic synthesis process. The anticancer activities of the synthesized compounds were evaluated using the MTT assay in MCF-7 and L929 cell lines, and some derivatives (3d, 3h, 3k, 3n) exhibited selective cytotoxicity. The inhibitory effects of these compounds on the aromatase enzyme were determined and compared with those of letrozole. Molecular docking studies were performed to investigate the interactions of the most active compounds with the aromatase enzyme's active site, revealing binding energies and amino acid interactions. Finally, the ADME profiles of the lead compounds were assessed to analyze their pharmacokinetic properties. The findings suggest that the selected triazole derivatives may be promising novel candidates for aromatase inhibition in breast cancer therapy.

Pediatric asthma is a common chronic condition with several pathological features, including airway inflammation, remodeling, and oxidative stress. Rutaecarpine (RUT), a bioactive alkaloid, exhibits therapeutic efficacy against various allergic diseases. However, its roles in asthma and the underlying molecular mechanisms remain elusive. In this study, we established an ovalbumin (OVA)-induced mouse model of asthma. The results showed that compared with the OVA-challenged group, treatment with RUT (10 and 20 mg/kg) reduced lung tissue inflammatory scores by 37.5% and 50.0%, respectively. Additionally, RUT suppressed the production of interleukin (IL)-4, IL-5, and IL-13, and decreased the counts of total cells, eosinophils, macrophages, neutrophils, and lymphocytes in bronchoalveolar lavage fluid. Regarding airway remodeling, RUT downregulated the mRNA and protein expression of α-smooth muscle actin and type I collagen. Furthermore, periodic acid-Schiff staining showed that RUT ameliorated OVA-induced mucus hypersecretion. RUT treatment also exhibited a protective effect on OVA-induced oxidative damage in lung tissues. Mechanistically, RUT suppressed OVA-induced activation of the nuclear factor-kappa B (NF-κB) pathway. Collectively, RUT attenuated inflammation, airway remodeling, and oxidative stress in OVA-induced asthmatic mice by inhibiting the NF-κB pathway, highlighting its potential as an adjunct therapy for pediatric asthma and providing a theoretical basis for future clinical translation.

Osteoarthritis (OA)-associated pain, driven by M1 macrophage polarization and inflammation, lacks effective therapies. Tetrahydropalmatine (THP), known for its anti-inflammatory and analgesic properties, was evaluated for its effects on OA-induced pain and macrophage polarization. A destabilization of the medial meniscus (DMM)-induced OA mouse model and lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages were used. Behavioral tests, histology, immunofluorescence, enzyme-linked immunosorbent assay (ELISA), reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting (WB), and immunohistochemistry (IHC) were used to assess pain, inflammation, and the expression of lysine demethylase 4A (KDM4A), murine double minute 2 (MDM2), and hypoxia-inducible factor-1α (HIF-1α). THP treatment alleviated OA-induced pain and cartilage damage and reduced CD86 expression, and reduced the expression of pro-inflammatory factors tumor necrosis factor-α (TNF-α), inducible nitric oxide synthase (iNOS), interleukin-6 (IL-6), and key signaling molecules (KDM4A, MDM2, and HIF-1α). Mechanistically, KDM4A directly bound to the MDM2 promoter and activated its transcription via H3K9me3 demethylation, whereas MDM2 enhanced HIF-1α signaling to promote M1 polarization. Overexpression of KDM4A reversed the inhibitory effects of THP on MDM2/HIF-1α signaling and inflammation. These findings indicate that THP mitigates OA-associated pain and inflammation by blocking KDM4A-mediated MDM2 transcription and suppressing HIF-1α-dependent M1 macrophage polarization, highlighting the KDM4A-MDM2-HIF-1α axis as a potential therapeutic target.

Idiopathic pulmonary fibrosis (IPF) is a chronic, progressive fibrosing interstitial lung disease without any effective treatment. Berberine (BBR), a botanical alkaloid, possesses extensive biological activities and has significant therapeutic value in various diseases. However, the effect and potential mechanisms of BBR on pulmonary fibrosis remain elusive. In vivo, BBR was administered by gavage following intratracheal instillation of bleomycin (BLM) in a mouse model from Day 1 to Day 20. In vitro, Human Lung Fibroblast (HLF) and A549 cell lines were used to explore the effects of BBR on transforming growth factor β1 (TGF-β1) treated cells. Both cell lines were transfected with a lentivirus carrying TGF-β receptor 2 (TGFBR2) knockdown genes, and the autophagy inhibitor chloroquine (CQ) and PI3K inhibitor LY294002 were employed to investigate the underlying effects of BBR on TGF-β signaling and autophagy in pulmonary fibrosis. BBR administration attenuates pulmonary inflammation and fibrosis of BLM-induced mice in vivo. Analogously, BBR treatment significantly alleviates matrix collagen deposition and reduces the expression of fibrotic markers in TGF-β1-treated human lung fibroblasts (HLF) and alveolar epithelial cell (A549) in vitro. Mechanistically, we found that BBR downregulates the expression of TGFBR2 and suppresses TGF-β/Smad2/3 signaling in vivo and in vitro. Furthermore, BBR inhibits the activation of the PI3K/AKT/mTOR pathway and autophagy, then downregulates the expression of pro-fibrotic genes. The effect of BBR on pulmonary fibrosis was further verified using both TGF-β1-treated HLF and A549 cells with the addition of the inhibitors of PI3K, LY294002, and autophagy, CQ in vitro, respectively. Our study suggests that BBR can inhibit pulmonary fibrosis by down-regulating the expression of TGFBR2, attenuating TGF-β/Smad2/3 signal, and activating autophagy through phosphorylation of PI3K/AKT/mTOR.

Diabetes mellitus and gastrointestinal infections remain major global health concerns, contributing to high morbidity, mortality, and economic burden. To address these challenges, a series of oxadiazole-bearing imine scaffolds were designed and synthesized as dual α-glucosidase and urease inhibitors. Among them, compound 5 (IC₅₀ = 5.30 ± 0.20 μM for α-glucosidase; 8.60 ± 0.30 μM for urease) and compound 6 (IC₅₀ = 3.80 ± 0.60 μM; 5.20 ± 0.40 μM) exhibited the most potent inhibitory activity. The in vitro potential of these compounds was compared with the standard compounds urease (IC₅₀ = 12.20 ± 0.21 μM) and acarbose (IC₅₀ = 10.30 ± 1.10 μM). All compounds were synthesized and characterized using ¹H NMR, ¹³C NMR, and HREI-MS. In silico studies, including molecular docking, revealed strong binding interactions between the active molecules and target enzymes. Density Functional Theory (DFT) analysis provided insights into electronic characteristics such as HOMO-LUMO energy gaps and reactive molecular regions, while ADMET profiling confirmed favorable drug-likeness. Pharmacophore modeling of compound 6 highlighted critical hydrogen-bonding interactions, and molecular dynamics simulations further validated the stability and affinity of the protein-ligand complexes. Collectively, these findings suggest that the synthesized oxadiazole derivatives are promising dual inhibitors with potential therapeutic relevance in diabetes and gastrointestinal infections.

Acquired resistance to 5-fluorouracil (5-FU) is a primary clinical challenge in colorectal cancer (CRC) treatment. Our study aimed to identify key factors predictive of 5-FU resistance and to elucidate their functional mechanisms by combining multi-omics analysis with experimental verification. The prognostic model was constructed based on the gene expression omnibus (GEO, GSE196900, GSE166555) and the cancer genome atlas (TCGA)-Colon Adenocarcinoma (COAD) datasets combined with regression analysis. Kaplan-Meier (K-M), receiver operating characteristic (ROC) curve, and nomogram were used to evaluate the predictive performance of the prognostic model. Gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) were used for functional enrichment analysis. Single-cell RNA sequencing (scRNA-seq, GSE166555) and qRT-PCR analysis were used to analyze the tumor microenvironment and gene expression. In cell experiments, CCK-8 assay measured IC₅₀ value. Glycolysis metabolism was evaluated by detecting glucose consumption, lactic acid production, extracellular acidification rate (ECAR), and oxygen consumption rate (OCR); cell stemness was evaluated by sphere formation assay. A 5-gene prognostic model was successfully constructed, which could effectively distinguish the high-/low-risk groups of CRC patients and was significantly correlated with overall survival. Ribosome binding protein 1 (RRBP1) is highly expressed in cancer tissues of non-responders to chemotherapy. It is also highly expressed in tumor epithelial cells, and its high expression is closely related to aneuploidy characteristics, up-regulation of oncogenes, and activation of pro-survival pathways. In vitro experiments confirmed that knockdown of RRBP1 significantly enhanced the sensitivity of CRC cells to 5-FU and inhibited cell proliferation. Mechanistically, RRBP1 knockdown effectively reversed the enhanced glycolysis activity and stem cell-like properties of 5-FU-resistant cells. This study established RRBP1 as a key CRC prognostic factor and 5-FU resistance driver, operating through the regulation of cell glycolysis and stemness. RRBP1 emerges as a new biomarker and therapeutic target for predicting the efficacy of 5-FU.

In a world where cancer continues to be a major health problem, the urgency continues to find new effective treatments. This work involved the synthesis of more than 10 anticancer fluoroquinolones (FQs) and pyridoquinoxaline (PQ) derivatives originating from FQs and studied their cytotoxicity, anti-adhesion, anti-invasion, and pro-apoptotic properties. Synthesis of the new compounds of the PQ series was carried out by reacting 1-cyclopropyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylic acid with L-proline, 3 and 4-hydroxy proline derivatives (compounds 2a-2f), followed by reductive cyclization to yield compounds 3a-3f. Compounds 2a and 3a gave favorable activities on MCF-7 with respective IC₅₀ values of 5.9 and 0.9 μM, respectively, while the hydroxy derivatives almost lost activity on all tested cells. Due to the fact that the activity of PQs and precursor FQs was correlated to increased lipophilicity, the lipophilic FQs series 10a, 10b, 11a, and 11b were prepared by direct reaction of 1-cyclohexyl-6-fluoro-8-nitro-4-oxo-1, 4-dihydroquinoline-3-carboxylate with chloro or fluoro aniline, followed by ester hydrolysis 10a and 10b and reduction to yield the amine compounds 11a and 11b. All FQs 10a, 10b, 11a, and 11b showed very excellent cytotoxicity against all tested cell lines (mammary MCF-7, MDA-MB-231, and invasive prostate DU-145) with IC₅₀ values below 20 μM with impressively favorable lack of any cytotoxicity in normal ligament PDL fibroblasts (in 3.125-200 μM). Only FQs exerted comparable or superior anti-adhesion and anti-invasion activity versus the antineoplastic reference quercetin. Significant incremental increases in the pro-apoptogenesis Bax/anti-apoptosis Bcl ratio revealed a physiologically regulated cytotoxicity via DNA fragmentation harvested in cytolysates. The structure activity relationship (SAR) and quantitative structure activity relationship (QSAR) reveal that planarity due to a fused polycyclic system and lipophilicity were essential requirements for anticancer PQs, whereas a high number of hydrogen bonds (HBs) and increased number of chelators, in addition to lipophilic balance, are the major requirements for anticancer FQs. In vitro cell viability assays revealed pronounced affinity for reductions in cell viabilities for the targeted PQ-bearing AuNPs versus PQsalone (induced) incubations and basal (non-induced) controls after 48 h incubation with HT29 cells. These results are very promising upon optimization of the system.

Baicalein, one of the active ingredients of banxia xiexin decoction, has good therapeutic efficacy in treating diarrhea and improving gastrointestinal dysfunction. The role and mechanism of Baicalein on irinotecan (CPT-11)-induced gastrointestinal dysfunction are the focus of this study. Concretely, CPT-11 induced delayed diarrhea rat model and intestinal epithelial cell (IEC)-6 cell injury model with Baicalein treatment as needed. Colonic pathological changes were analyzed by hematoxylin-eosin staining, and inflammatory factor expressions in serum were determined by enzyme-linked immunosorbent assay. Immunohistochemistry and western blot were performed to quantify ferroptosis-related protein expressions. Thiobarbituric acid reactive substances (TBARS) kits and colorimetric assay kit were applied to detect lipid peroxidation levels and Fe²⁺ content, respectively. In vitro experiments also included quantitative real-time polymerase chain reaction, cell counting kit-8, and C11 BODIPY staining. CPT-11 induced aggravation of intestinal tissue damage, inflammatory factor release, Fe²⁺ accumulation, upregulation of lipid peroxidation and 15-Lipoxygenase (ALOX15) expression, and downregulation of glutathione peroxidase 4 (Gpx4) and SLC7A11 in vivo in rats; however, Baicalein dose-dependently reversed the effects of CPT-11. Baicalein elevated cell viability, reduced lipid peroxidation and Fe²⁺ accumulation, and elevated Gpx4 and SLC7A11 levels, whereas ALOX15 overexpression reversed the effects of Baicalein on a CPT-11-induced IEC-6 cell injury model. In conclusion, Baicalein plays a mitigating role in CPT-11-induced delayed diarrhea via ALOX15-mediated ferroptosis.

Pouzolzia zeylanica (L.) Benn. is a Chinese herbal medicine widely used for its anti-inflammatory and pus-removal properties. To explore its potential anti-inflammatory mechanism, quercetin 3,7-dirhamnoside (QDR), the main flavonoid component of P. zeylanica (L.) Benn., was extracted and purified. The potential anti-inflammatory targets of QDR were predicted using network analysis. These potential targets were verified using molecular docking, molecular dynamics simulations, and in vitro experiments. Consequently, 342 potential anti-inflammatory QDR targets were identified. By analyzing the intersection between the protein-protein interaction and the Kyoto Encyclopedia of Genes and Genomes (KEGG) pathways, we identified several potential protein targets of QDR, including RAC-alpha serine/threonine-protein kinase (AKT1), Ras-related C3 botulinum toxin substrate 1 (RAC1), nitric oxide synthase 3 (NOS3), serine/threonine-protein kinase mTOR (mTOR), epidermal growth factor receptor (EGFR), growth factor receptor-bound protein 2 (GRB2), and endothelin-1 receptor (EDNRA). QDR has anti-inflammatory activity and regulates immune responses and apoptosis through chemokines, Phosphatidylinositol 3-kinase 3(PI3K)/AKT, cAMP, T-cell receptor, and Ras signaling pathways. Molecular docking analysis showed that QDR has good binding abilities with AKT1, mTOR, and NOS3. In addition, molecular dynamics simulations demonstrated that the protein-ligand complex systems formed between QDR and AKT1, mTOR, and NOS3 have high dynamic stability, and their protein-ligand complex systems possess strong binding ability. In RAW264.7 macrophages, QDR significantly inhibited lipopolysaccharides (LPS)-induced inducible nitric oxide synthase expression, nitric oxide (NO) release and the generation of proinflammatory cytokines IL-6, IL-1β, and TNF-α. QDR downregulated the expression of p-AKT1(Ser473)/AKT1 and p-mTOR (Ser2448)/mTOR, and upregulated the expression of NOS3, Rictor, and Raptor. This indicates that the anti-inflammatory mechanisms of QDR involve regulation of AKT1 and mTOR to prevent apoptosis and of NOS3 which leads to the release of endothelial NO. Thus, our study elucidated the potential anti-inflammatory mechanism of QDR, the main flavonoid found in P. zeylanica (L.) Benn.