Anti-cancer agents in medicinal chemistry最新文献

Introduction: Benzochromenes are heterocyclic compounds of growing interest in medicinal chemistry due to their diverse biological activities, including antioxidant, anticancer, and antimicrobial properties.

Methods: A one-pot, three-component synthesis was employed to prepare benzochromene derivatives (4a-f) using 2-naphthol or its derivatives, active methylene compounds, and 2-methoxybenzaldehyde in ethanol with piperidine as a catalyst. The compounds were evaluated for their anticancer activity against MCF-7, HepG-2, and HCT-116 cell lines, as well as for their antimicrobial activity through molecular docking studies targeting cancerrelated and microbial proteins.

Results: All synthesized compounds were obtained in moderate to good yields. Compounds 4c, 4e, and 4f demonstrated superior biological activity compared to standard drugs Doxorubicin and Augmentin. Docking studies revealed strong binding affinities to key targets, including the TGF-βI receptor and the choline-binding domain.

Discussion: The hydroxyl group at position 9 in compounds 4c and 4f likely contributed to enhanced antimicrobial activity, while the bromo group in 4e correlated with significant anticancer effects. These findings suggest meaningful structure-activity relationships and validate the design strategy.

Conclusion: The synthesized benzochromene derivatives exhibit promising anticancer and antimicrobial activities. Supported by molecular docking, these findings lay the groundwork for further pharmacological and in vivo evaluations of this scaffold.

Introduction: Aromatase inhibition is one of the most effective strategies for the treatment of ER+ breast cancer, which accounts for about 70% of breast cancer cases. Indole-based aromatase inhibitors have altered the dynamics of the search for anti-breast cancer drugs with efficacy in nanomolar concentrations. In the present study, we have integrated pharmacophore mapping with Gaussian-based 3D-QSAR analysis to map the essential pharmacophoric features of indole-based aromatase inhibitors, aiming to optimize lead molecules.

Methods: Pharmacophore mapping and Gaussian-based 3D-QSAR were integrated to identify the steric and electrostatic features essential for aromatase inhibitory activity.

Results: A Gaussian-based 3D-QSAR model with an r² value of 0.7621 and stability of 0.817 was generated to determine the nature of substitutions essential for optimal biological activity. Pharmacophore mapping results indicated that H-bond Donor (D), a Hydrophobic (H) feature, and three aromatic rings are essential for potent inhibitory activity.

Discussion: In order to identify important structural characteristics of indole-based aromatase inhibitors, the current study successfully integrated pharmacophore mapping investigations with 3D-QSAR. The developed molecule S1 demonstrated activity comparable to letrozole, with a predicted pIC50 value of 9.332 nM.

Conclusion: The designed compound S1 demonstrated a predicted IC50 value of 9.332 nM, comparable to the most active compound 15 and the standard reference Letrozole. The developed models may be utilized by medicinal chemists for the optimization of new indole-based aromatase inhibitors for the effective treatment of ER+ breast cancer.

Prostate cancer, timosaponin A‑III, apoptosis, autophagy, reactive oxygen species, AMPK/mTOR.

Introduction: Timosaponin A-III (TAIII) is an effective anti-tumor ingredient extracted from the rhizomes of Anemarrhena asphodeloides. However, the effect of TAIII on prostate cancer cells (PCa) and its underlying mechanisms is rarely investigated. The current study aimed to investigate the anti-tumor effect and potential mechanisms of TAIII in PCa cells.

Methods: The effect of TAIII on the cell proliferation of PCa was evaluated by CCK-8 assay, colony formation assay, and EDU assay. Cell apoptosis and reactive oxygen species (ROS) production were evaluated by flow cytometry. The puncta of LC3 were detected by immunofluorescence analysis. The protein levels of apoptosis, autophagy, and AMPK/mTOR pathway were assessed by western blot. Finally, a PC3 xenograft nude mouse model was constructed to determine the effect of TAIII combined with chloroquine (CQ) in vivo.

Results: Our data showed that TAIII inhibited the proliferation of PCa cells and induced ROS-dependent apoptosis. TAIII treatment dramatically promoted the formation of LC3-positive puncta, and increased the expression of LC3B-II and P62 protein. Moreover, the combination of TAIII with CQ significantly enhanced the pro-apoptosis effect of TAIII in PCa cells and the PC3 xenograft model. In addition, the activation of the AMPK/mTOR pathway and the induction of autophagy induced by TAIII were reversed by Compound C. Suppressing AMPK with Compound C enhanced the apoptosis induced by TAIII in PCa cells.

Discussion: This study establishes TAIII as a potent anti-prostate-cancer agent that kills tumor cells via ROSdriven apoptosis while simultaneously triggering cytoprotective autophagy through the AMPK-mTOR axis. However, TAIII's clinical potential awaits pharmacokinetic, bioavailability, and toxicity evaluation.

Conclusion: TAIII induced ROS-mediated cell apoptosis and promoted cytoprotective autophagy via the AMPK/mTOR pathway in PCa. These findings may provide a new strategy for combining TAIII with CQ together for PCa treatment.

Endometrial carcinoma (EC) is one of the most prevalent gynecological malignancies, with an increasing incidence globally. This review explores the role of molecular markers in revolutionizing the diagnosis, prognosis, and management of EC. This article provides an overview of endometrial carcinoma, emphasizing its subtypes and the molecular mechanisms driving disease progression. Current biomarkers, while clinically significant, often present limitations in sensitivity, specificity, and predictive value, necessitating the discovery of novel markers. Recent advances in genetic and epigenetic profiling have identified key mutations, such as PTEN, TP53, and POLE, along with DNA methylation patterns and microRNAs, as crucial contributors to EC pathophysiology. Furthermore, transcriptomic and proteomic studies reveal the potential of RNA-based markers (e.g., lncRNAs, mRNAs) and proteomic signatures in improving early diagnosis and prognostic predictions. Immunohistochemical markers and insights into tumor microenvironment dynamics pave the way for targeted therapeutic strategies. In the context of endometrial carcinoma (EC), clinical trials play a pivotal role in validating targeted therapies based on molecular subtypes and biomarkers, such as HER2 amplification, POLE mutations, and mismatch repair deficiency (MMRd). This review underscores the integration of biomarkers into precision oncology, enabling personalized treatment regimens. However, challenges such as barriers to clinical translation and the need for advanced technologies highlight the importance of continued research in marker discovery for EC.

Background: To explore the possibility of a combination of dabrafenib and SHP2 inhibitor in the treatmentof anaplastic thyroid carcinoma and to provide a new therapeutic strategy for the treatment of anaplastic thyroid cancer.

Methods: Firstly, a drug resistance model was established, and the expression levels of related RTK were detected byqPCR. Western blot was used to detect the protein expression levels of Akt and MAPK signaling pathways in the control group, single-drug group and two-drug combination group. The gene silencing of SHP2 was achieved by transfection of siRNA and verified by Western blot. CCK8 kit and clone formation assay were used to detect cell proliferationactivity. In vivo model of mutant thyroid cancer cells was established by subcutaneous injection of mice and then divided into four groups. Tumor diameter was measured every two days. Immunohistochemistry was used to evaluate theexpression of p-ERK, p-AKT and Ki67 in mouse tumors.

Results: In this study, dabrafenib-resistant ATC cells were first constructed, and the response of RTKs in drug-resistant cells was upregulated to activate Akt and MER/ERK pathways. The activation of Akt and MEK/ERK pathways in the combination group was significantly inhibited, and the proliferation ability of tumor cells was significantlyreduced compared with Dabrafenib, SHP099 group and DMSO group. To verify that SHP099 was not off-target, we also silenced SHP2 expression by transfection with siRNA and obtained the same results. Finally, by building a mouse drug resistance model, we confirmed that dabrafenib and SHP099 can also play a powerful anti-cancer effect in vivo.

Conclusion: The SHP2 inhibitor SHP099 can effectively reverse the drug resistance of dabrafenib through inhibitingthe reactivated RAS signaling pathway in anaplastic thyroid cancer. The combination of dabrafenib with SHP2 inhibitor has shown significant tumor suppressive effects for dabrafenib-resistant cells and it may be a new therapeutic strategy with longer lasting therapeutic benefits.

Introduction: Lung cancer progression involves complex interactions between metabolic pathways and the immune microenvironment. The role of serotonin, a tryptophan-derived metabolite, in immune responses to lung tumors remains unclear.

Methods: An orthotopic lung cancer model was established by intravenously injecting KP (KrasG12D/p53-/-) cells into C57BL/6 mice. Metabolomic and flux analyses were conducted on tumor versus normal lung tissues. Serotonin was administered to tumor-bearing mice, followed by immunofluorescence and flow cytometry to assess immune responses. Human lung cancer datasets were analyzed to validate clinical relevance.

Results: Tumor tissues exhibited a significant decrease in serotonin levels. Although tryptophan, serotonin, and kynurenine levels were decreased overall, flux analysis revealed a metabolic shift favoring kynurenine synthesis, with a ~10-fold increase in the kynurenine-to-serotonin ratio. Serotonin supplementation significantly prolonged survival and enhanced dendritic cell and CD8⁺ T cell infiltration and activation in tumors. Analysis of public datasets showed that serotonin expression positively correlated with CD8⁺ T cell activation signatures and patient prognosis.

Discussion: By revealing serotonin as a potential biomarker and therapeutic target, this study paves new avenues for improving lung cancer treatment strategies through modulation of the immune microenvironment. Moreover, the precise receptor-mediated mechanisms underlying serotonin's immunomodulatory effects remain to be clarified, and translational validation in human tissues is warranted to strengthen clinical relevance.

Conclusion: Serotonin deficiency in the tumor microenvironment of the lung suppresses antitumor immunity. Its restoration reverses immune dysfunction and limits tumor progression. These findings identify serotonin as a potential metabolic regulator and immunotherapeutic target in lung cancer.

Introduction: Breast cancer develops in breast tissues, in ducts and lobules. It affects both genders, though it is uncommon in men. Hematological variations are important considerations and deficiencies in metals can negatively impact human health. Cadmium is highly toxic and plays role in breast cancer progression. This study was designed for hematological variations and cadmium induced toxicity in mice and humans causing breast cancer.

Methods: Mice, obtained from local supplier, housed at university laboratory for 11 weeks, exposed to cadmium. Following dissection, blood and organs were harvested for examination. Histological analysis of liver and mammary gland tissues was conducted.

Results: Affected mice had higher Hb, RBC, HCT, MCV, and MCH, while humans showed lower Hb, HCT, and MCV but similar RBC and MCH. Other blood values also show changes. Histopathology revealed changes in mammary glands (higher cadmium led to increased fat deposition, degeneration of alveolar epithelial cells, and a reduction in alveolar milk lumen size, indicating compromised glandular function) and Liver damage (vacuolation, lipid accumulation, fibrosis, and collagen deposition, was noticeable with prolonged cadmium). These changes causes liver fibrosis and impaired mammary gland function.

Discussion: The cadmium exposure induces distinct hematological alterations and severe tissues damage, reflecting species-specific responses. The observed liver fibrosis and mammary gland dysfunction emphasize cadmium's potential to compromise critical organ functions over time.

Conclusion: Significant effects of cadmium exposure in mice were observed. Histological damage was seen in mammary glands and liver. Further research on protective measures and dose-response relationships for cadmium exposure is needed.

Introduction: This study aims to identify the key genes and pathways associated with sotorasib resistance in Non-Small Cell Lung Cancer (NSCLC) using bioinformatics analyses and experimental validation, with a focus on uncovering the potential mechanisms underlying resistance.

Methods: We compared gene expression profiles between sotorasib-resistant (SR) and non-resistant NSCLC cell lines using the GSE229070 dataset and between NSCLC tissues and adjacent normal tissues using the GSE18842 dataset. Differentially expressed genes (DEGs) were identified and intersected across datasets using the Venn diagram package. Functional enrichment analysis was performed using the Database for Annotation, Visualization, and Integrated Discovery (DAVID). The transcriptional activity and prognostic impact of key genes were evaluated using the UALCAN portal and Kaplan-Meier Plotter, respectively. The correlation between gene expression and immune cell infiltration was analyzed using the TIMER database, and co-expressed genes were explored using LinkedOmics. qRT-PCR and Western blot were used to validate the expression of AREG in parental and SR cell lines.

Results: We identified 33 overlapping DEGs, including TENM2, COL12A1, COL5A2, and LRRC15 (upregulated) and AREG (downregulated). AREG expression was significantly lower in NSCLC patients and associated with worse survival outcomes. AREG expression was also correlated with the levels of immune cell infiltration. Functional enrichment analysis revealed that AREG was associated with pathways including the NOD-like receptor signaling pathway, focal adhesion, DNA replication, and homologous recombination. Experimental validation confirmed that AREG mRNA and protein levels were significantly reduced in HCC78-SR cells compared to parental HCC78 cells.

Discussion: The downregulation of AREG is closely associated with sotorasib resistance in NSCLC, potentially contributing to resistance through alterations in signaling pathways and the tumor immune microenvironment. This finding aligns with previous studies on AREG's role in drug resistance, highlighting its potential as a therapeutic target. However, limitations include reliance on publicly available datasets and the need for further validation in clinical cohorts.

Conclusion: The study identifies AREG as a key gene associated with sotorasib resistance in NSCLC, suggesting its potential as a biomarker and therapeutic target. Further research is needed to elucidate the mechanisms underlying AREG's role in resistance and to explore its clinical significance.

Introduction: Cancer metastasis and associated thrombosis are significant contributors to cancerrelated mortality, necessitating therapeutic strategies that simultaneously address both issues. This study aimed to evaluate the dual anti-metastatic and anti-hypercoagulability properties of dHG-5, a low-molecular-weight fucosylated glycosaminoglycan derived from the sea cucumber Holothuria fuscopunctata.

Methods: The heparanase-inhibitory and anticoagulant effects of dHG-5 were assessed in vitro using biochemical assays. The impact of dHG-5 on 4T1 cell migration and invasion was evaluated using Transwell assays. The antimetastatic and anti-hypercoagulability efficacy of dHG-5 was further tested in a 4T1 mammary carcinoma mouse model, with enoxaparin (LMWH) used as a control.

Results: dHG-5 exhibited potent heparanase inhibition (IC50 = 91.0 nM) and significantly reduced 4T1 cell migration and invasion at 4.0 μmol/L. In vivo, dHG-5 reduced lung metastasis without affecting tumor growth or proliferation. At a dose of 20 mg/kg, dHG-5 prolonged activated partial thromboplastin time (APTT) from 23.5 ± 1.85 s to 30.4 ± 3.36 s, effectively reversing hypercoagulability in tumor-bearing mice. Compared to lowmolecular- weight heparin, dHG-5 selectively prolonged APTT with negligible effects on prothrombin time and thrombin time.

Discussion: The findings highlighted the dual-action mechanism of dHG-5, namely inhibiting heparanase and selectively targeting the intrinsic coagulation pathway. This selective action minimized bleeding risk, a common issue with traditional anticoagulants. However, this study focused on a single cancer type and the use of a mouse model, which may not fully represent human pathophysiology. We would explore dHG-5's effects across different cancer types and investigate its potential synergistic effects with existing cancer therapies in the future.

Conclusion: dHG-5 suppressed metastasis and hypercoagulability through heparanase inhibition and selective action on the intrinsic coagulation pathway. These findings highlight dHG-5 as a promising dual-action therapeutic candidate for managing metastasis and cancer-associated thrombosis, offering a safer alternative to traditional anticoagulants.

Introduction: Current research focuses on identifying and analyzing bioactive metabolites with significant therapeutic properties derived from Punic granatum L. (Pomegranate) leaves.

Methods: The biological potential of these metabolites was evaluated through anticancer activity. In contrast, LC-QTOF-MS and GC-QTOF-MS methods were used to profile the metabolites. In silico molecular docking was performed using various online and offline tools to validate the active metabolites.

Results: PAC exhibited significant anticancer activity. The identified metabolites were screened, and 40 compounds from different categories were chosen for further in silico interaction studies.

Discussion: The molecular docking analysis discovered lead molecules that exhibited promising binding energy scores, efficiency, and stable modulation with specific protein domains. However, clinical trials are required for the applications of the lead molecules in the design of anticancer drugs.

Conclusion: The findings from both in vitro and in silico analyses support the notion that the P. granatum Acetone Extract (PAC) is an excellent source of potential metabolites with therapeutic properties. According to the findings, this research enhances the treatment of human breast cancer and validates several plant traditions for their numerous benefits.