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Ten previously unreported highly oxygenated sesquiterpenoid glucoside esters (1-10), named cissvolubicins A-J, were isolated from the aerial parts of Cissampelopsis volubilis by bio-guided isolation. All compounds feature a sesquiterpenoid core that is linked to either a disubstituted or monosubstituted glucopyranose moiety, which is rare in Nature. The structures as well as absolute configurations of these compounds were elucidated through a combination of NMR, HRESIMS, chemical methods, single-crystal X-ray diffraction, calculations of ECD and DP4+ technologies. Structurally, the aglycones of 1-5 were identified as cadinane-type sesquiterpenoid class, the aglycone of 6 (5/6-fused ring) was characterized as uncommonly rearranged sesquiterpenoid, and the aglycones of 7-10 were assigned to the eudesmane-type sesquiterpenoid class. Compounds 1-10 were assessed for their cytotoxic effects on TNBC cells, specifically MDA-MB-231 and HCC1806. Among them, compounds 1, 5, and 6 exhibited pronounced anti-TNBC activity, with 50% inhibitory concentration values between 3.5 and 7.6 μM. Evaluation of structure-activity relationships displayed that the absence of oxygenation at C-3 was a key determinant of anti-TNBC potency among cadinane-type sesquiterpenoid glucosides. Additionally, 1 markedly suppressed TNBC cell growth and motility, induced cell cycle arrest and apoptosis, and effectively inhibited tumor growth in both xenograft models in vivo and organoid models in vitro. Mechanistic investigations using molecular docking as well as western blot analyses confirmed that 1 directly interacts with RAS and inhibits ERK activation. Collectively, these findings identify cadinane-type sesquiterpenoid glucoside esters as anti-TNBC agents with therapeutic potential for the first time.

In search of epidermal growth factor receptor (EGFR)-targeted anticancer agents for non-small cell lung carcinoma (NSCLC) therapy, new thiazolyl hydrazones were synthesized and tested for their cytotoxic features on A549 human lung adenocarcinoma and L929 embryonic fibroblast cells. Among them, compounds 2a, 2d, 2e, 2h, 2j and 2k exhibited the most promising cytotoxic activity against A549 cell line with the IC50 values of 20.51, 29.24, 23.06, 13.70, 5.36 and 22.50 μM, respectively, compared to erlotinib (IC50 = 64.65 μM). The selectivity indices (SIs) of compounds 2a, 2d, 2e, 2h, 2j and 2k were determined as 3.32, >4.27, 4.13, 2.95, 14.01 and 3.76, respectively. These agents were advanced for the preparation of nanoparticle (NP) formulation, and subsequently both the free compounds and their NP formulations were subjected to in vitro mechanistic studies, including flow cytometry-based analysis of apoptosis, ELISA-based EGFR inhibition, and real-time polymerase chain reaction (RT-PCR) analysis in A549 cell line. The NP formulations of compounds 2a, 2d and 2k exerted marked cytotoxicity through the induction of apoptosis and inhibition of EGFR. The NPs of compounds 2a and 2k reduced EGFR mRNA expression in A549 cells. Moreover, the NP of compound 2a was able to notably decrease CYD1 mRNA expression. Based on molecular docking studies, compounds 2a and 2k interact with the Met769 residue in the EGFR TK binding site similarly to erlotinib. In silico pharmacokinetic data suggest that both agents possess favorable pharmacokinetic profiles. Taken together, compounds 2a and 2k can be considered potential antitumor agents for EGFR-targeted NSCLC therapy.

Skin pigmentation disorders present a significant therapeutic challenge, often arising from disturbances in melanin metabolism that lead to uneven pigmentation and skin damage. Tyrosinase (TYR), the key enzyme in melanin biosynthesis, serves as a crucial therapeutic target for managing hyperpigmentation and pigmentary skin diseases. In this study, we performed structure-based virtual screening of a comprehensive library of FDA-approved drugs and chemical active agents against tyrosinase and selected top-ranked compounds based on predicted binding affinities and favorable binding poses for experimental validation. In vitro assays confirmed that nine compounds inhibited mushroom tyrosinase (mTYR) with IC50 values of 6.3-23.4 μM. Among them, rosmarinic acid (compound 1) and ferulic acid (compound 3) also inhibited human tyrosinase (hTYR) with IC50 values of 7.8 ± 0.4 and 9.3 ± 0.5 μM, respectively. Enzyme kinetic analysis indicated a competitive inhibition mechanism against mTYR for the most active compounds. In α-melanocyte stimulating hormone (MSH)-stimulated B16F10 cells, the selected hits produced measurable anti-melanogenic effects within the tested concentration range, with cellular IC50 = 37.8-108.1 μM. Additionally, molecular dynamics simulations of rosmarinic acid in complex with hTYR confirmed a stable binding mode characterized by persistent coordination within the dicopper active site. These findings identify repurposable small-molecule scaffolds with tyrosinase-inhibitory activity and highlight rosmarinic acid as a promising lead for further development. Although the present study is limited to in vitro enzymatic and cellular evaluation, it provides a useful foundation for future validation in human skin-derived systems and in vivo models.

Cancer remains the second leading cause of death globally, primarily because of the shortcomings of existing treatments, which include early drug resistance, metastasis, inadequate pharmacokinetics, and systemic toxicity. Small-molecule inhibitors that target the interaction of MDM2 and p53 show promise for reactivating p53 function and suppressing tumor growth. In this study, we designed, produced, and evaluated a number of 2-(4-((2,4-difluorobenzylidene)amino)-5-mercapto-4H-1,2,4-triazol-3-yl)phenol derivatives as possible anticancer agents utilizing both in silico and in vitro approaches. All obtained compounds showed effective binding interactions, as evidenced by their high docking scores. Molecular dynamics (MD) simulations validated the structural stability, compactness, and rigidity of the most active molecule during a 100 ns time period. ADMET predictions indicated good pharmacokinetic parameters and low toxicity profiles, whereas DFT investigates validated the compounds' reactive features and electronic compatibility for biological activity. The structures of the synthesized compounds were confirmed through 1H NMR, 13C NMR, IR, and ESI-MS analyses. The anticancer activity in vitro was assessed using the MTT assay on MCF-7 and A549 cell lines. Of all the compounds tested, compound 8D, N-(benzo[d]thiazol-2-yl)-2-((4-((2,4-difluorobenzylidene)amino)-5-(2-hydroxyphenyl)-4H-1,2,4-triazol-3-yl)thio)acetamide, exhibited the strongest activity against MCF7 & A549 cells, with an IC₅₀ value of 7.56 & 7.22 μM respectively. This study identifies a new class of small-molecule inhibitors that interact with p53 and MDM2, characterized by low toxicity and high efficacy, which could be turned into anticancer drugs. These findings are essential for medicinal chemists and researchers working on the discovery of anticancer medicines.

The therapeutic efficacy of cytarabine (Ara-C) in anaplastic large cell lymphoma (ALCL) is frequently compromised by dose-limiting myelosuppression and drug resistance. To address this, we developed a series of novel 1,2,3-triazole-dithiocarbamate hybrids designed to target Aurora A kinase and enhance chemosensitivity to Ara-C. Compound 22h emerged as the lead candidate, exhibiting potent Aurora A inhibition (IC₅₀ = 0.296 μM) with threefold preferential inhibition over Aurora B (IC₅₀ = 0.887 μM) and sub-micromolar activity against ALK (IC₅₀ = 0.332 μM). Molecular docking and 100-ns molecular dynamics simulations suggest that 22h engages a putative allosteric pocket in Aurora A, centered on Cys290 (S-score -13.67 kcal/mol), conferring superior stability over ATP-site binding, while simultaneously forming stable interactions within the ALK hinge region. In ALK+ ALCL SR cells, 22h demonstrated significant cytotoxicity (IC₅₀ = 5.10 μM) and high tumor selectivity (SI = 7.0) relative to normal peripheral blood mononuclear cells. Mechanistically, 22h induced potent G₂/M arrest (3.2-fold increase), supporting Aurora A as the primary functional target, alongside cellular ALK depletion as a complementary mechanism. Furthermore, it triggered mitochondrial apoptosis (17.8% total apoptotic fraction) and dismantled chemoresistance pathways by elevating intracellular ROS (3.5-fold) and inhibiting ALDH1 activity (IC₅₀ = 2.8 μg/mL). Crucially, co-treatment with 22h synergistically potentiated Ara-C efficacy (Combination Index = 0.78), reducing the Ara-C IC₅₀ by 12.8-fold (from 27.65 μM to 2.15 μM) and dramatically widening the therapeutic window by 14-fold (SI = 29.6). These findings identify 22h as a novel multi-target scaffold with potent Aurora A/ALK inhibitory activity that restores Ara-C sensitivity in ALCL, supporting its further development as a precision chemosensitizer.

This study aimed to investigate whether Astragaloside-Brucea javanica oil nanoemulsion (AS/BJO-NEs) inhibits the malignant progression of oral squamous cell carcinoma (OSCC) and to further explore its potential regulatory mechanisms. Immunohistochemistry (IHC) was used to evaluate the expression of related pathway proteins in human OSCC and adjacent normal tissues. Stable OSCC cell lines with knockdown or overexpression of CDK1/HOXC10 were established. The effects of AS/BJO-NEs and the underlying mechanisms were assessed in vitro through colony formation, wound healing, and Transwell invasion assays, as well as RT-qPCR, western blot, chromatin immunoprecipitation (ChIP), and dual-luciferase reporter assays. An OSCC subcutaneous xenograft model in nude mice was constructed for in vivo validation using RT-qPCR, western blot, hematoxylin and eosin (H&E) staining, and IHC. Analysis of clinical samples revealed upregulated expression of CDK1, P-EZH2, HOXC10, MTFR2, and N-cadherin, alongside downregulated expression of H3K27me3 and E-cadherin in OSCC tissues. In vitro experiments confirmed that AS/BJO-NEs downregulated CDK1 in a concentration-dependent manner, subsequently reducing the expression of P-EZH2, HOXC10, and MTFR2, increasing H3K27me3 levels, and inhibiting cell proliferation, migration, and invasion. H3K27me3 was enriched in the HOXC10 promoter region, and HOXC10 directly bound to and activated MTFR2 transcription. In vivo experiments demonstrated that AS/BJO-NEs effectively inhibited tumor growth, regulated molecules within this pathway and epithelial-mesenchymal transition (EMT) markers, whereas CDK1 overexpression counteracted these effects CONCLUSION: This study demonstrates that AS/BJO-NEs exert anti-OSCC effects by inhibiting CDK1, downregulating HOXC10, thereby reducing MTFR2 expression, and suppressing cell proliferation, migration, invasion, and the EMT process.

Radioactive iodine-resistant thyroid cancer (RAIR-TC) poses diagnostic and therapeutic challenges due to the absence of sodium/iodide symporter (NIS) expression. This study aims to evaluate the preclinical value of 89Zr-DFO-EDB and 177Lu-DTPA-EDB, an antibody fragment targeting fibronectin EDB (FN-EDB), in the theranostics of RAIR-TC. A CAL-62 human iodine-resistant thyroid cancer xenograft mouse model was established. The EDB antibody fragment (approximately 100 kD), selected through phage display technology, was labeled with 89Zr and 177Lu, respectively. The targeting characteristics of 89Zr-DFO-EDB and 177Lu-DTPA-EDB in the CAL-62 and NIS-silenced models were analyzed using dynamic micro-PET/CT imaging and ex vivo biodistribution. The anti-tumor efficacy and safety were assessed by a single treatment with 100 μCi of 177Lu-DTPA-EDB. The labeling efficiency of 89Zr-DFO-EDB was 90.9%, with a radiochemical purity (RCP) of >99% and stability >98% at 180 min. Imaging showed that tumor uptake peaked at 72 h (13.8 ± 3.32%ID/g) and the liver was the main metabolic organ. High tumor uptake (16.1 ± 1.85%ID/g) was observed in the NIS-silenced model, confirming that EDB antibody targeting is independent of NIS status. The labeling efficiency of 177Lu-DTPA-EDB was 87.7%, with an RCP of >98.6% and stability >95% at 48 h. In the treatment group, tumor volume decreased by 78.5%, with a relative proliferation rate T/C of 25.05% (<40%). Pathological examination revealed necrosis areas >65%, with only transient weight loss (5.2%) and mild hepatocyte degeneration observed. 89Zr-DFO-EDB and 177Lu-DTPA-EDB achieved precise theranostics of RAIR-TC by targeting EDB-FN, with excellent imaging contrast and significant therapeutic effects, providing an innovative strategy for clinical translation in NIS-negative thyroid cancer.

Pyruvate Kinase M2 (PKM2) is a central regulator of glucose metabolism in cancer cells whose function extends beyond glycolysis. PKM2 can translocate to the nucleus, where it acts as an oncogenic transcription factor. In turn, its nuclear retention is enhanced upon binding with poly(ADP-ribose), which is prevented by PARP1 inhibition. To exploit this interplay, a new class of PKM2-PARP1 inhibitor conjugates was designed and synthesized. The lead compound 9f potently inhibited PKM2 and PARP1 (IC50 = 261 ± 23 nM and 39.5 ± 3.1 nM, respectively). 9f also reduced PKM2 dimerization, lowered nuclear accumulation, and selectively downregulated PKM2 mRNA. Functionally, 9f demonstrated broad antiproliferative activity across multiple cancer cell lines (IC50 = 2.9-6.6 μM) and completely inhibited 3D cancer cell spheroid formation at 12.5 μM. These findings establish PKM2-PARP1 conjugates as a novel class of dual inhibitors that impair PKM2 at enzymatic, nuclear, and transcriptional levels, extending PARP inhibition strategies beyond their established role in DNA-repair pathways.

Focal adhesion kinase (FAK) is frequently overexpressed in colorectal cancer (CRC) and plays a pivotal role in tumor progression, making it an attractive therapeutic target. Although FAK inhibitors effectively suppress its kinase activity, they fail to block its non-enzymatic functions. Most reported FAK-targeting proteolysis targeting chimeras (PROTACs) have primarily focused on optimizing degradation efficiency, often with limited emphasis on the FAK warhead itself. Herein, a series of novel FAK-targeting PROTACs were designed and synthesized through systematic optimization of both the warhead moiety and linker composition. Among these, compound 16 g emerged as the most potent degrader, exhibiting an IC50 value of 1.56 μM against HCT116 colorectal cancer cells while showing no cytotoxicity toward normal L02 cells. Western blot analysis confirmed that 16 g induced dose-dependent degradation of FAK protein in HCT116 cells. Furthermore, 16 g significantly suppressed colony formation and demonstrated anti-angiogenic activity by inhibiting HUVEC cell proliferation. These findings establish compound 16 g as a novel and potent FAK degrader with promising therapeutic potential for colorectal cancer.

KRAS-mutant tumors remain a major challenge in cancer therapy. Although current targeted drugs show initial promise, their efficacy is often limited by the development of resistance. Therefore, identifying effective drug combinations to target KRAS-mutant tumors is of great significance. This study investigates the synergistic potential of romidepsin (RO), a class I HDAC inhibitor, in combination with adagrasib (ADA). In vitro experiments demonstrated that RO exhibits potent antitumor activity, with significant efficacy against KRAS-mutant cells. Mechanistic studies revealed that RO exerts its effect by suppressing NRF2. More importantly, its combination with ADA enhanced cytotoxicity and further suppressed NRF2 expression, resulting in increased ROS levels, induction of cytotoxic autophagy, and inhibition of the downstream AKT pathway. In vivo xenograft models confirmed that the combination of RO and ADA significantly reduced tumor growth. These findings suggest that RO and ADA act synergistically against KRAS-mutant tumors by suppressing NRF2, supporting their potential as a targeted combination strategy for KRAS-driven cancers.