Chemical Biology & Drug Design最新文献

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.

Eight new LQFM's Aplysinopsin analogs (12a-h) were synthesized and were evaluated for their anticancer profile on MCF-7 (breast cancer), SiHA and HeLa (cervical cancer). The compounds were obtained through the rational drug design strategy, bioisosterism, by changing the indole scaffold of Aplysinopsin by phenylpyrazole, a subunit extensively explored for designing potent and selective anticancer agents. The synthesis was performed in three simple steps, followed by structural elucidation through nuclear magnetic resonance, infrared spectroscopy, and mass spectrometry, and global yield ranged from 10% to 93%. Regarding the biological assay, the best result was achieved with 12g, which showed antiproliferative activity against all cell lines evaluated, with IC₅₀ 59.22, 58.33, and 55.32 μM for MCF-7, SiHA and HeLa, respectively. The safety profile, in the Zebrafish-based model, showed the mortality rate for 12g in concentration-time-dependent, from 87 μM, over 120 h. All Aplysinopsin analogs demonstrated drug-likeness in agreement to Lipinski and Veber rules. Although the moderate antiproliferative activity displayed by 12g, our results include new Aplysinopsin analogs that may be promising lead compounds for further studies, since chemical structures related to this marine compound have provided satisfactory results as anticancer agents against a variety of human tumor cell lines.

The interaction of small molecule drugs with human serum albumin (HSA) after entering the human blood circulation system profoundly affects their distribution and absorption in the body, and further influences the activity. Thus, the in-depth investigation of drug interactions with HSA is of great significance for the optimization of drug candidates, the research and development of new drugs, and the risk assessment and control of drug combinations. Phenolic acids and flavonoids are valuable in antioxidant, antitumor, immunomodulatory studies, and many other fields, which is of great value in clinical medication. Here, the binding behaviors of 12 phenolic acids/flavonoids to HSA under physiological conditions were simultaneously investigated by affinity capillary electrophoresis (ACE) method and fluorescence spectroscopy for the first time. Results showed the binding behaviors of 12 substances were related directly to their structures. Even a little change, such as the amount of phenolic hydroxyl groups and an extra C=C bond, the binding would significantly change. Among them, rosmarinic acid (K_a = 3.880 × 10⁵ M⁻¹, n = 1.074, Sudlow site I) showed the best binding ability. Caffeic acid trended to bind with Sudlow site II, which meant it could cooperate with the other active phenolic acids/flavonoids (like dihydromyricetin and rosmarinic acid) in clinical medication to increase the curative effect. Fluorescence method verified the accuracy of the results determined by ACE. However, it showed some limitations such as fluorescence interference, indicating it was not suitable for some determinations. These provide a new reference for the screening of potential inhibitors for anticancer and antidiabetic agents.

Salidroside has been reported to have various pharmacological activities, including hypoxia tolerance, anti-radiation, and antitumor. In this study, we studied the antitumor activity of salidroside ether derivatives in the human hepatocellular carcinoma cell line Hep3B. We created eleven new benzyl halide derivatives called S1–S11 by modifying the phenolic hydroxyl groups at the C4 position of salidroside. The compounds were shown to inhibit tumor proliferation in the in vitro CCK-8 assay. Compounds S4, S5, S6, S7, S8, and S11 demonstrated strong inhibitory activity anti-human hepatic cancer cell Hep3B, with IC₅₀ values of 67.89, 97.55, 73.67, 57.92, 88.29, and 33.39 μM, respectively. Under the inverted microscope, compared with the blank group, after 48 h of administration, it showed obvious proliferation inhibition and apoptosis characteristics. In addition, network pharmacology predicts that these derivatives may have the effect of regulating the nervous system and protecting neuronal cells without violating Lipinski's Rule. In summary, the benzyl halide modification on the C4 phenolic hydroxyl group on the benzene ring of SAL can improve its antitumor activity, which provides ideas for the subsequent development of salidroside antitumor drugs.