Chemical Biology & Drug Design最新文献

Hepatocellular carcinoma (HCC), the most common subtype of primary liver cancer, remains a major cause of cancer-related mortality worldwide. Although 2-hydroxy-3-methylanthraquinone (HMA), a natural anthraquinone compound, has demonstrated antitumor activity in various malignancies, its specific role and underlying mechanisms in HCC are not fully understood. This study aimed to evaluate the antitumor effects and molecular mechanisms of HMA in HCC. Human HCC cell lines were treated with HMA, and cell proliferation and apoptosis were assessed using Cell Counting Kit-8 and flow cytometry assays, respectively. A heterotopic xenograft tumor model was established in nude mice to evaluate in vivo tumor growth and weight. Immunohistochemical staining for Ki67 and Terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) assay was performed to assess tumor cell proliferation and apoptosis. Network pharmacology analysis was conducted to predict potential targets of HMA in HCC. Quantitative real-time polymerase chain reaction and Western blotting were used to evaluate mRNA and protein expression levels. Cell migration and invasion were assessed using wound healing and transwell assays. Our data revealed that HMA significantly suppressed cell proliferation, induced apoptosis, and inhibited migration and invasion in both HCC cells and tumor tissues. Mechanistically, HMA downregulated Annexin A5 (ANXA5) expression and inhibited activation of the phosphatidylinositol 3-kinase/protein kinase B (PI3K/AKT) signaling pathway. Silencing of ANXA5 replicated the inhibitory effects of HMA and further enhanced its pro-apoptotic and anti-invasive activities. Conversely, overexpression of ANXA5 restored PI3K/AKT signaling activity and reversed the inhibitory effects of HMA on HepG2 cell proliferation, migration, and invasion. These reversal effects were abolished by treatment with LY294002, a selective PI3K inhibitor. In summary, HMA suppresses the progression of HCC by targeting ANXA5 and inhibiting the PI3K/AKT signaling pathway, highlighting its potential as a novel therapeutic agent for HCC.

Platinum-based and pyrimidine drugs are first-line treatments for gastric cancer (GC), but their efficacy is often affected by drug resistance. High spalt-like transcription factor 4 (SALL4) expression is associated with poor prognosis, but its role in 5-fluorouracil (5-FU) resistance is not yet clear. In this study, we investigated the effect of SALL4 on 5-FU resistance in GC cells by bioinformatics analysis, real-time quantitative reverse transcription polymerase chain reaction, cell counting kit-8, colony formation assay, and western blot. The results showed that SALL4 was highly expressed in GC and significantly correlated with the fatty acid oxidation (FAO) pathway. Knockdown of SALL4 resulted in a notable attenuation of cellular proliferative capacity and heightened susceptibility to 5-FU resistance in GC cells, while overexpression of SALL4 enhanced 5-FU resistance. Rescue assays confirmed that SALL4 fostered 5-FU resistance in GC cells by enhancing FAO. Our research confirmed that SALL4 promoted the resistance of GC cells to 5-FU by enhancing the FAO pathway. This suggests that drug development targeting SALL4 may help overcome chemotherapy resistance in GC.

A new group of thiadiazole-benzenesulfonamide hybrids was designed, synthesized, and biologically evaluated as potential dual inhibitors targeting B-Raf and VEGFR-2 for cancer therapy. The cytotoxic activity of the synthesized derivatives was assessed against HepG2 and Huh7 liver cancer cell lines, where compound 7a exhibited the most potent activity with IC₅₀ values of 17.89 μM and 25.07 μM, respectively. The kinase inhibition assay revealed that 7a strongly inhibited both B-Raf (IC₅₀ = 0.11 μM) and VEGFR-2 (IC₅₀ = 0.15 μM), surpassing sorafenib in B-Raf inhibition. Further mechanistic studies revealed that 7a induced G2/M phase arrest, with a significant increase in late apoptotic cells (57.08%) compared to the control group (0.15%), confirming its pro-apoptotic effect. The apoptotic pathway was further validated by caspase-3 activation, Bax upregulation, and Bcl-2 downregulation. Computational analyses verified the effective binding of compound 7a to VEGFR-2. These analyses included molecular docking, molecular dynamic (MD) simulations, molecular mechanics with generalized Born and surface area solvation (MM-GBSA), protein-ligand interaction fingerprints (ProLIF), principal component analysis (PCAT), and free energy landscape (FEL) studies. Additionally, DFT studies indicated 7a's stability and reactivity. In silico ADMET predictions indicated that the derivatives had good absorption, were non-mutagenic, non-carcinogenic, and exhibited low toxicity risks compared to sorafenib. These findings suggest that the synthesized thiadiazole-benzenesulfonamide hybrids, particularly 7a, represent promising dual BRAF/VEGFR-2 inhibitors with potent anti-cancer activity, warranting further optimization and preclinical evaluation.

A series of new linear pyrazole-based tetrazole derivatives 1–10 were synthesized and characterized. The structures of the intermediate compounds were confirmed using ¹H and ¹³C NMR spectroscopy, as well as high-resolution mass spectrometry (HRMS). These derivatives were synthesized through a straightforward equimolar condensation between pyrazole and tetrazole precursors. The vasorelaxant activity of these compounds was assessed by determining their percentage inhibition, E (%), which ranged from 26% to 67%, with compound 4 exhibiting the highest activity. Additionally, their anti-diabetic potential was evaluated by determining the IC₅₀ values for α-amylase enzyme inhibition. Notably, compounds 2 and 6 demonstrated a comparable activity to the positive control acarbose. These experimental findings were further supported by molecular docking studies.

Studies documented by our lab established ZNF726 to potently augment the tumorigenic behavior of breast cancer cells by increasing cellular cholesterol levels. Therefore, Zinc finger protein 726 (ZNF726) can be considered an attractive therapeutic target for the treatment of breast cancer. Based on these views, this study aimed to identify potent inhibitors targeting ZNF726 activity utilizing a structure-based molecular docking method. Virtual screening with the LOPAC library led to the identification of zoledronic acid monohydrate as a top-hit compound featuring good docking and MMGBSA scores. Further, zoledronic acid monohydrate was found to inhibit the proliferation potential of breast cancer cells. Ectopic expression of ZNF726 led to an increase in the cholesterol levels of breast cancer cells. Further, this study confirms that zoledronic acid tends to decrease the cholesterol content in ZNF726-overexpressed cells along with an inhibitory effect on breast cancer cell proliferation. Conclusively, these findings suggested that the cholesterol pathway and oncogenic ZNF726 form an interdependent relationship, and therefore, targeting the cholesterol pathway may prove to be a promising strategy to inhibit oncogenic ZNF726 expression in breast cancer. Additionally, this study also reveals nine phytochemicals that might target ZNF726 activity, identified through virtual screening by the IMPPAT library. Three phytochemicals (Swertiamacroside, Terflavin A, and N-(3-Carboxy-2,3-dihydroxypropyl)-4-((carboxymethyl)amino) threonine) out of the nine phytochemicals are still unknown for their anticancer role which needs further exploration. Briefly, this study draws attention toward finding potential therapeutics against the carcinogenic effects of ZNF726 by multiple in silico approaches.