Chemical Biology & Drug Design最新文献

A series of new pyrazole/quinoline hybrids 11a–n was constructed and synthesized as prospective antiproliferative agents. The antiproliferative activities of the newly synthesized hybrids were assessed against a panel of four human cancer cells: HT-29, A-549, Panc-1, and MCF-7. Hybrids 11c, 11d, 11h, 11i, and 11k demonstrated remarkable antiproliferative activity, with IC₅₀ ranging from 36 to 61 nM, compared to erlotinib, which had IC₅₀ ranging from 30 to 40 nM. Hybrid 11i was the most potent EGFR inhibitor with an IC₅₀ of 87 nM and exhibited comparable EGFR inhibition to that of erlotinib (IC₅₀ = 80 nM). Molecular docking study results in the EGFR active site agreed with the EGFR inhibitory activity results.

The Hedgehog pathway may be involved in chronic obstructive pulmonary disease (COPD). Its inhibitor, Vismodegib, has therapeutic potential, but the underlying mechanisms require further investigation. A COPD mouse model was established using lipopolysaccharide (LPS) and cigarette smoke exposure, with concurrent Vismodegib intervention. Assessments included histopathology, pulmonary function, inflammatory cytokines, neutrophil extracellular traps (NETs) markers, macrophage polarization, and integrated transcriptomic and gut microbiota (16S rRNA) analysis. The results show that Vismodegib alleviated lung injury and fibrosis, regulated the respiratory rate, reduced the levels of pro-inflammatory cytokines such as interleukin (IL)-6 (IL-6), IL-1β, and tumor necrosis factor-α (TNF-α), promoted a phenotypic shift from M1 to M2 macrophage polarization, and suppressed NETs formation, as demonstrated by decreased levels of neutrophil elastase (NE), citrullinated histone H3 (Cit-H3), myeloperoxidase (MPO), and Cit-H3⁺Ly6G⁺ cells. Multi-omics analysis revealed enrichment of the IL-17 signaling pathway and increased gut microbial abundance of Bacteroidaceae and Tannerellaceae. Vismodegib may alleviate inflammation and tissue damage in COPD by inhibiting NETs-mediated M1 polarization of macrophages. This study is the first to propose the targeting of NET-driven macrophage polarization via Hedgehog inhibition as a novel therapeutic strategy for COPD, providing a new mechanistic framework for drug repurposing.

Viral infections are a global cause of serious morbidity and mortality. The recent COVID-19 pandemic further testifies to the continued need to develop novel classes of antiviral agents with broad activity and high selectivity. In this work, 5-(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) bearing a methyl or ethyl group at position 1- of the indole ring were synthesized. Along with previously synthesized compounds 5a-j, 5l, 6b-d, 6g, 6i, and 6k-n, the novel compounds 5k, 6a, 6e, 6f, 6h, 6j, and 6o were evaluated in cytopathic effect (CPE) reduction assays with a broad range of DNA and RNA viruses. Favorable activity was observed in human embryonic lung (HEL) fibroblast cells infected with herpes simplex virus type 1 (HSV-1, wild type or thymidine kinase-deficient) and type 2, or with vaccinia virus (VV). In general, the ethyl substituted compounds (6a–o) had higher antiviral activity and lower cytotoxicity than the methyl substituted analogues (5a–l). The antiviral potency was markedly enhanced by substitution at position 4- of the phenyl ring, with the analogues bearing a 4-methyl (6c), 4-fluoro (6l), or 4-chloro (6n) moiety exhibiting average EC₅₀ values of 1.6 to 6.6 μM against HSV-1, HSV-2, and VV, besides selectivity indices (i.e., ratio of cytotoxic over antiviral concentration) of 21–40. Within the series bearing a substituent at position 3-, the trifluoromethyl analogue 6d was unique in suppressing human adenovirus type 2 (AdV-2) and coronavirus HCoV-229E. To conclude, our study highlights the versatility and relevance of the 5-(trifluoromethoxy)-1H-indole-2,3-dione 3-(4-phenylthiosemicarbazones) for developing antiviral agents against different virus families.

VEGFR-2 is a critical target in cancer therapy, facilitating tumor angiogenesis, yet existing inhibitors face toxicity and resistance issues. Chrysin, a flavonoid with anticancer properties, has VEGFR-2 characteristics but suffers from poor pharmacokinetics. A series of 7-O-substituted chrysin derivatives was designed to improve binding and drug-like properties by integrating key hydrogen-bonding groups and hydrophobic elements, informed by VEGFR-2 structural analysis. To design and assess novel chrysin derivatives through computational predictions and molecular docking; synthesize and characterize selected derivatives; and evaluate their antioxidant and anticancer activities in vitro, to identify effective candidates that exhibit favourable pharmacokinetics and safety. Chrysin derivatives featuring alkylamino and ester substituents were designed using molecular docking against VEGFR-2. ADMET profiling was conducted to anticipate pharmacokinetics and toxicity. In silico cytotoxicity of chrysin and its hybrids was assessed using CLC-Pred 2.0 on the basis of PASS analysis and further analyzed on nine breast cancer cell lines via BC CLC-Pred. Selected derivatives were synthesized via alkylation and esterification and characterized using UV, IR, NMR, and mass spectrometry. Antioxidant activity was evaluated with the DPPH assay, whereas anticancer efficacy against MCF-7 and normal cell lines was measured through cell viability assays, comparing IC₅₀ values to ascorbic acid and sorafenib. Docking studies indicated strong binding affinities, particularly for ester derivatives. ADMET predictions suggested favorable drug-like characteristics. Compound C7 demonstrated remarkable antioxidant activity (IC₅₀ = 0.6 μM), exceeding both chrysin and ascorbic acid. In anticancer tests, C7 and C8 displayed significant cytotoxicity (IC₅₀ = 1.0 and 1.5 μM, respectively), outperforming chrysin and nearing sorafenib efficacy. All other hybrids were found to have moderate inhibitory properties as compared to sorafenib, but better than chrysin. The improved bioactivity and predicted safety of C7 and C8 highlight the efficacy of rational structural modifications in optimizing natural products. Their dual antioxidant and anticancer properties underscore their potential as lead compounds for VEGFR-2-targeted breast cancer treatments. Ester-substituted chrysin derivatives, specifically C7 and C8, demonstrate promising VEGFR-2 inhibition and therapeutic potential, warranting further exploration as multifunctional anticancer agents.

Twenty-six novel derivatives of paeonol chalcone were synthesized by introducing various hydrophilic aminoalkyl to the 2′-hydroxy of paeonol. Their antiproliferative activity was evaluated by MTT assay against five human cancer cell lines (HeLa, HepG2, U2OS, HCT-116 and A549). The majority of these compounds demonstrated remarkable cytotoxicity against the tested cancer cells. Among them, compound 4k exhibited the most potent antiproliferative activity (IC₅₀ values ranging from 1.31 μM to 7.56 μM for the tested cancer cells), stronger than 5-FU (IC₅₀ = 6.29–14.56 μM). Notably, it effectively inhibited the proliferation of HeLa/Taxol cells (IC₅₀ = 14.47 ± 0.02 μM) while showing low cytotoxicity toward normal liver epithelial THLE-2 cells (IC₅₀ = 26.40 ± 0.04 μM). Preliminary mechanistic studies revealed that compound 4k induces apoptosis in HeLa cells and downregulates the expression of Cyclin B1 and CDK1, leading to cell cycle arrest at the G2/M transition. Solubility studies revealed that 5k (4k hydrochloride) showed excellent aqueous solubility (11.53 mg/mL). SwissADME predictions further supported its potential druggability. Collectively, compound 4k represents a promising lead worthy of further investigation as a potential antitumor agent.

Lung squamous cell carcinoma (LUSC) has a poor prognosis due to the lack of effective targeted therapies, and its incidence has increased dramatically in recent years, creating an urgent need for new prognostic markers. Given that tumor immune and metabolic heterogeneity can influence LUSC prognosis, this study aimed to construct a novel predictive model based on immune-related and metabolism-related genes for prognostic stratification in LUSC. Transcriptomic as well as clinical data of 502 and 43 LUSC cases were downloaded from The Cancer Genome Atlas Program (TCGA) and the Gene Expression Omnibus (GEO) databases. Core LUSC subtype genes were identified using nonnegative matrix factorization (NMF), and a prognostic risk model was subsequently constructed by applying machine learning, LASSO regression, and multivariate Cox regression. Based on this model, patients were stratified into low-risk and high-risk subgroups with distinct expression profiles and significant survival differences. Gene-Set Enrichment Analysis of the marker genes revealed that immune pathways were active in the high-risk group, whereas metabolic pathways were prominent in the low-risk group. The two groups also differed in tumor mutation burden and response to clinical therapy. High expression levels of NRTN, CYP2C18, TSLP, MIOX, and RORB and low expression levels of HBEGF, SERPIND1, PTGIS, and LBP were correlated with high survival rates. Immunohistochemical validation in 42 patients confirmed the expression patterns of the identified genetic markers, which were stronger in tumor tissues than in adjacent normal tissues. In conclusion, six immune-related and three metabolism-related genes were identified as prognostic markers of LUSC, with their expression levels significantly associated with the survival rate. The resulting model demonstrates strong predictive power and is expected to help guide treatment strategy decisions.

Problems such as high toxicity, low selectivity, and drug resistance encountered in cancer treatment increase the need for more effective and safe anticancer agents. In this study, the anticancer effects of new compounds consisting of thiazole and 1,3,4-thiadiazole derivatives were investigated. Compound 6e, which showed the strongest cytotoxic effect, was evaluated in detail in human bladder (HTB-9) and lung (A549) cancer cells. According to the WST-1 test results, the IC₅₀ value of compound 6e was determined as 38.9 μM for HTB-9 cells and 82.86 μM for A549 cells. As a result of Annexin V-FITC/PI double staining and flow cytometry analysis, it was determined that compound 6e application significantly increased the apoptotic cell rates in both HTB-9 and A549 cells. It was observed that it significantly induced early apoptosis in HTB-9 cells and late apoptosis in A549 cells (p < 0.0001). Caspase-3/7 activity was significantly increased in HTB-9 cells after compound 6e application compared to the control group and similarly increased in A549 cells (p < 0.0001). In cell cycle analyses, compound 6e caused cell cycle arrest in the G2/M phase in HTB-9 and A549 cells. In the wound healing test, the migration speed in HTB-9 and A549 cells treated with compound 6e after 24 h was significantly decreased (p < 0.0001). Molecular docking revealed strong binding to caspase-3 (PDB ID: 1NMQ, score: −8.2 kcal/mol), identifying key interactions that mechanistically support its pro-apoptotic effects. In addition, the low cytotoxicity of compound 6e in healthy BEAS-2B cells suggests that it has a selective anticancer effect.

Osteosarcoma is a prevalent form of cancer that develops in growing bones. The precise cause of this multifaceted disease remains uncertain. Yet, genetic, genomic and proteomic research has enhanced our understanding of the disruption in its molecular signaling pathways. In this review, we attempted to highlight the regulation of autophagy pathways by a range of biocompounds (chemical compounds of biological origin) in osteosarcoma. Autophagy is a degradation mechanism, maintaining cellular homeostasis under basal and stress conditions. However, the role of autophagy is variable in cancer. There is a delicate balance between autophagy and apoptosis, and disruption of this balance is one of the causes of tumor formation and development. Autophagy and apoptosis can reciprocally activate or inhibit each other. Thus, autophagy works synergistically or antagonistically with apoptosis. In osteosarcoma, different biocompounds involve in the regulation of autophagy and/or apoptosis, triggering cellular signaling pathways, convenient or inconvenient for growth, proliferation, invasion and metastasis of cancer cells in a tumor. Also, some of the biocompounds have been shown to affect the therapeutic response of osteosarcoma cells. Therefore, biocompounds are promising candidates for the regulation of autophagy and may play critical roles in the crosstalk between autophagy and apoptosis in osteosarcoma.