Deep eutectic solvents have good biodegradability, low volatility, and efficient reusability. In the present work, deep eutectic solvents were used as solvents and catalysts to promote the cyclization reaction of sulfonylhydrazine compounds with (3-dicarbonyl compounds, which is highly efficient and easy to operate. In addition, the post-treatment is simple without complicated post-processing such as column chromatography purification. The new synthesis process has good versatility. It is suitable for industrialized-scale production.

This study systematically investigated the inhibitory mechanism of four catechin monomers (EGC, ECG, EC, and EGCG) against lipase using cyclic voltammetry (CV) and molecular docking. Electrochemical analysis revealed that the redox behavior of EGCG is modulated by solution pH and scan rate. The EGCG–lipase system exhibited quasi-reversible redox characteristics at pH 6.86 and 4.00, whereas the redox signal completely disappeared under pH 9.18, suggesting possible irreversible covalent binding. Scan-rate experiments showed that the redox peak potential difference (ΔEp from 77mV to 184 mV) of the EGCG increased markedly with increasing scan rate (from 10mV/s to 100 mV/s), and the change was more pronounced than that of EGCG–lipase complex (ΔEp from 75mV to 124 mV) at PH 6.86, indicating that lipase binding hinders electron diffusion. Molecular docking results demonstrated that the four catechins form two binding pockets in lipase (PDB: 1LBS): EGCG specifically occupies the left pocket, while EGC, ECG, and EC share the right pocket. The binding energies followed the order: ECG (–8.6 kcal/mol) > EGCG (–8.1 kcal/mol) ≈ EGC (–8.1 kcal/mol) > EC (–7.0 kcal/mol). All catechins bind near the catalytic triad of lipase via non-covalent interactions. ECG formed the most non-covalent interactions, consistent with its stronger binding affinity. Integrating electrochemical and computational evidence, this work elucidates a pH-dependent inhibition mechanism: reversible non-covalent complexation dominates under acidic and neutral conditions, whereas alkaline pH may promote irreversible covalent inhibition. It findings provide a theoretical basis for the anti-obesity potential of catechins and offer a multiscale methodological framework for studying natural product–enzyme interactions.

Phosgene is a highly toxic chemical warfare agent that continues to pose a serious threat to public health and safety, thereby creating a strong demand for rapid, sensitive, and reliable onsite detection methods. Among currently available analytical approaches, fluorescent probes offer distinct advantages, including high sensitivity, high selectivity, fast response, and operational simplicity, which make them particularly attractive for phosgene monitoring. This review summarizes small-molecule fluorescent probes for phosgene detection with well-defined sensing mechanisms reported since 2020. Particular emphasis is placed on the fundamental relationships among response mechanism, reaction type, fluorophore architecture, and recognition site. On this basis, a mechanistic framework integrating sensing mechanism, reaction pathway, and analytical performance is proposed to clarify the structure–property relationships underlying successful probe design. It is anticipated that this review will provide a useful reference for the rational design of next-generation and high-performance fluorescent probes for phosgene detection.

Small ubiquitin-like modifier (SUMO) conjugation, or SUMOylation, is a dynamic post-translational modification that regulates protein stability, localization, transcriptional activity, DNA damage response, and cellular stress adaptation. Increasing evidence indicates that dysregulated SUMOylation contributes to tumor progression, immune disorders, and neurodegenerative diseases, highlighting the SUMO pathway as a promising therapeutic target. However, despite extensive advances in SUMO biology, a comprehensive pharmacological assessment of SUMO pathway inhibitors, including their mechanisms of action, evidence quality, target engagement, and translational challenges, remains insufficient. This review presents an inhibitor-centered analysis of pharmacological strategies targeting the SUMOylation machinery. This review describes the molecular architecture of the SUMO conjugation cycle and identifies major druggable nodes, including the SUMO-activating enzyme (SAE), the SUMO-conjugating enzyme UBC9, SUMO-specific proteases (SENPs), and SUMO-dependent protein–protein interactions. It also examines the biological rationale for SUMO pathway inhibition in major disease contexts, with an emphasis on cancer, autoimmune disorders, and neurological diseases. Furthermore, SUMO pathway modulators are systematically classified according to their molecular targets and evidence maturity, including SAE inhibitors, UBC9-directed compounds, SENP inhibitors, direct SUMO binders, and natural product-derived modulators. Their mechanisms of action, biochemical potency, structural validation, cellular target engagement, in vivo efficacy, PK/PD properties, and developmental status are critically evaluated. Overall, this review provides a comprehensive pharmacological framework for understanding SUMO pathway inhibition and highlights key considerations for the development of next-generation SUMO-directed therapeutics.

Berberine, an isoquinoline alkaloid isolated from the Chinese herb Coptis chinensis and other Berberis plants, exhibits a broad spectrum of pharmacological properties. It can inhibit the proliferation of various cancer cell types and impede invasion and metastasis. Benzenesulfonyl chloride or compounds containing the structure of benzenesulfonyl chloride have shown some potential in the development of anticancer drugs. In this study, a series of berberine benzenesulfonyl chloride couplings (compounds 4-59) was designed and synthesized based on berberine. Cell activity assays identified compounds 18 and 46 containing six methyl groups, as exhibiting significant anti-proliferative activity against lung cancer cell line H460 (compound 18: 4.50 & micro;M, compound 46: 10.82 & micro;M). Further assessment of the enzyme activity of these compounds against phosphoglycerate mutase 1 (PGAM1) demonstrated that compound 18 has an IC50 of 0.081 & micro;M, compound 22 has an IC50 of 0.076 & micro;M, and compound 35 has an IC50 of 0.087 & micro;M. The enzymatic activity of these three compounds is comparable to that of the positive control PGMI-004A, which has an IC50 of 0.052 & micro;M. These findings suggest that these compounds have potential as PGAM1 inhibitors. Compounds 18 and 46 were found to induce apoptosis, block the cell cycle at the G2/M stage, cause reactive oxygen species (ROS) to burst, and induce mitochondrial dysfunction. Importantly, compounds 18 and 46 down-regulated the expression of PGAM1 and up-regulated ACTA2 and P53 in the Western blot analyses. In conclusion, this study further provides a robust scientific foundation for the structural modification of berberine and the development of anti-lung cancer agents.

A temperature/light dual-stimuli-responsive polymeric carrier PPEGMA-b-PNIPAM-hv-PMAA-b-PS was designed and synthesized through host-guest mutual recognition, and further applied for pectinase immobilization. Both the host molecule PPEGMA-b-PNIPAM-β-CD and the guest molecule PS-b-PMAA-Azo were prepared via ATRP, hydrolysis, and click chemistry, respectively. The characterization of polymeric structure and morphology was carried out by 1H NMR, FTIR, and GPC. This polymer could self-assemble into spherical micelles in aqueous media, the critical micelle concentration (CMC) and the micellar morphology were also examined by UV-Vis, TEM, DLS, fluorescence spectra, etc. The enzyme immobilization property of the enzyme carrier was investigated too. It was revealed when pH was 4.0, immobilization concentration was 8 U/mL, temperature was 25 °C, and immobilization time was 60 min, both the immobilized amount and the relative activity could reach the maximum. By comparison with free pectinase, immobilized pectinase had a better tolerance to the variation of temperature and pH, and enhanced storage stability and reusability. Moreover, the relative activity of immobilized pectinase could be easily regulated by adjusting the temperature or UV irradiation. So, we can predict this immobilization material has a great application potential in industrial catalysis.

NQO1 is a FAD containing NAD(P)H-dependent oxidoreductase that catalyzes the reduction of quinones and related substrates, which plays an important role in the treatment of non-small cell lung cancer (NSCLC). Based on the indolequinone structure from 5-methoxy-2-methylindole, the indolequinone of NQO1 agonists was first coupled with amino-evodiamine derivatives by esterification reaction, and sixteen new compounds targeting NQO1 were developed. Among them, compounds 11b and 12d (IC50 = 2.72 or 3.66 mu M, respectively) were showed better activity by cytotoxicity assay than the reference drug EVO (IC50 = 19.65 mu M). Furthermore, the results of flow cytometry analysis showed that compounds 11b and 12d promoted apoptosis in A549 cells, blocked the cell cycle to the G2/M stage and caused a burst of reactive oxygen species. Western blotting experiments revealed that compounds 11b and 12d, after 24 h of treatment in A549 cells, downregulate the expression of Keap1 while upregulating the expression of Nrf2, NQO1, and HO-1. This suggests that compounds 11b and 12d increase cellular antioxidant capacity by regulating the Keap1/Nrf2/NQO1 antioxidant pathway. In vivo anti-tumor experiments showed that the reference drugs EVO (TGI = 15.94 %) and 5-Fu (TGI = 27.54 %) inhibited the proliferation of tumor tissue, while compound 11b could better inhibit the proliferation of tumor tissue (TGI = 39.13 %). In conclusion, our research results suggest that compounds 11b and 12d are potent agonism of the NQO1 signaling pathway and provide a potential opportunity to improve the treatment of NSCLC.

Isocitrate dehydrogenase 1 (IDH1) is a pivotal enzyme in cellular energy metabolism, playing a crucial role in the conversion of isocitrate into α-ketoglutarate (α-KG). When IDH1 undergoes mutation, it catalyzes the conversion of α-KG into the oncogenic metabolite 2-hydroxyglutarate (2-HG). Subsequently, 2-HG competitively suppresses a range of α-KG-dependent dioxygenase activities, ultimately leading to hypermethylation of DNA or histones, which in turn causes the occurrence of various malignant tumors, including acute myeloid leukemia (AML), glioma, and chondrosarcoma. Currently, the FDA has granted approval for the use of the small molecule inhibitor Ivosidenib (AG-120) in the treatment of IDH1-mutated AML and cholangiocarcinoma. Although AG-120 has benefited patients clinically, drug resistance has gradually emerged and has become a major problem in the treatment of mutant IDH1 (mIDH1) diseases. In this review, we highlighted the function of IDH1 mutations in cancer treatment and described detailed resistance mechanisms in terms of IDH1-specific mutation sites. Representative mIDH1 inhibitors and their binding modes were also discussed. In particular, we summarized seven strategies to overcome drug resistance, which provide a basis for understanding the mechanism of drug resistance for IDH1 mutations and exploring guidance to overcome drug resistance.

Formaldehyde (FA) is an active carbonyl structure that is widely used in people's daily life, such as preservatives and fixatives. Furthermore, formaldehyde is highly toxic and has been listed as one of the three major indoor pollutants. Therefore, the development of highly sensitive and selective fluorescent probes is of great biological importance. In this article, probe X is designed to identify formaldehyde by a light-induced electron transfer (PET) process between the naphthalimide derivative and the hydrazine group based on hydrazone formation. Moreover, the probe has good optical response and excellent linearity over a wide range of formaldehyde concentrations, ensuring that formaldehyde concentration values in real complex food samples can be quantitatively recorded. In addition, the probe can monitor the changes of formaldehyde levels in living cells with good biocompatibility and image resolution.

Signal transducer and activator of transcription 3 (STAT3) is closely related to a variety of cancers. The research of novel STAT3 inhibitors is an important and meaningful project for pharmaceutical chemist. In this study, 10 novel 1,4-naphthoquinones carrying 1,2,4-triazole derivatives were synthesized via a four-step synthesis starting from 2-hydroxynaphthalene-1,4-dione. The inhibitory activities of these compounds against four cancer cells were tested at concentrations of 10, 1, 0.1 μM. The results exhibited that compound S1 showed outstanding anti-tumor activity. In addition, we tested the inhibitory curves of compound S1 on four types of cells, containing HeLa, HepG2, U87, LN229, with the IC50 values of 5.066 μM, 0.8089 μM, 1.970 μM, and 1.412 μM, respectively. Moreover, we verified the mechanism of S1 targeted to STAT3 through Western blot and qPCR experiments. Based on the good anti-tumor activity of S1 in cell level, we also tested the blood-brain barrier (BBB) crossing rate and the preliminary pharmacokinetic properties, and the result demonstrated S1 can cross the BBB. The above research indicated that compound S1 has excellent anti-tumor activity, which is worth for further study.

Mutations in isocitrate dehydrogenase 1 (IDH1) have been widely observed in various tumors, such as gliomas and acute myeloid leukemia, and therefore has become one of the current research focal points. Therefore, it is crucial to find inhibitors that could target mIDH1, which may provide more effective treatment options for patients with related tumors. In present study, combines machine learning-based QSAR models and structure-based virtual screening to screen a series of potential IDH1 inhibitors from the Coconut databases. The QSAR model predictions indicate that the hit compounds have high binding affinity to the target protein, and its pIC50 value was found to be considerably larger than that of AGI-5198. The RMSD and Rg analysis demonstrated that all of the ligand-protein complexes exhibited a stable state throughout the simulation period. Furthermore, the binding free energy decomposition and per-residue contribution of the IDH1R132H-inhibitor complex revealed key fragments of the inhibitor interacting with residues ALA-111, PRO-118, ARG-119, LE-128, ILE-130, ITRP-267, VAL-281, and TYR-285 in the binding site of IDH1R132H. This investigation indicates that CNP0047068, CNP0029964, and CNP0025598 have the potential to be targeted inhibitors of IDH1R132H mutants through further optimization, providing new insights for discovering novel lead scaffolds in this domain.

Aldose reductase2 (ALR2), an activated enzyme in polyol pathway by hyperglycemia, has long been recognized as one of the most promising targets for diabetic complications especially in diabetic peripheral neuropathy (DPN). However, lots of ALR2 inhibitors showed serious side-effects due to poor selectivity over aldehyde reductase (ALR1). Herein, we described the discovery of a series of benzothiadiazine acetic acid derivatives as potent and selective inhibitors against ALR2 and evaluation of their anti-DPN activities in vivo. Compound 15c carrying carbonyl group at the 3-position of thiadiazine ring showed high potent inhibition against ALR2 (IC50 = 33.19 nM) and about 16109-fold selectivity for ALR2 over ALR1. Cytotoxicity assays ensured the primary biosafety of 15c. Further pharmacokinetic assay in rats indicated 15c had a good pharmacokinetic feature (T1/2 = 5.60 h, AUC(0-t) = 598.57±216.5 μg/mL*h), which was superior to Epalrestat (T1/2 = 2.23 h, AUC(0-t) = 20.43±3.7 μg/mL*h). Finally, in streptozotocin (STZ)-induced diabetic rat model, 15c significantly increased the nerve conduction velocities (NCVs) of impaired sensory and motor nerve, achieved potent inhibition of D-sorbitol production in the sciatic nerves, and significantly increased the paw withdrawal mechanical threshold (PWMT). Combined the above investigations, we proposed that 15c might represent a promising lead compound for discovery of anti-diabetic peripheral neuropathy drug.

Background: Shengxuebao mixture (SXBM) is a novel herbal drug approved by China State Food and Drug Administration for the treatment of Leukopenia and iron deficiency anemia caused by radiotherapy and chemotherapy . Methods: To explore the mechanism of SXBM in treating blood deficiency syndrome (BDS). Firstly, network pharmacology and in vivo experiments were used to screen candidate targets and important signaling pathways of SXBM, GO functional enrichment and KEGG pathway analysis were performed. Secondly, a BDS rat model was established to verify the results of the analysis of network pharmacological enrichment. Histopathology and routine peripheral blood examination were observed. The expressions of tumor necrosis factor-alpha, interleukin (IL)-6, HIF-1 alpha and NF- kappa B were detected by Western blot, and the expressions of IL-6, IL-1 beta were detected by ELISA . Results: 62 bioactive components, 66 potential targets and 131 signaling pathways of BDS were successfully identified by network pharmacology. Molecular docking simulation techniques showed that key targets tumor necrosis factor-alpha, IL-6, IL-1 beta can dock well with crucial components, and the BDS-related signaling pathways HIF-1 and JAK-STAT play a vital role. The combined model experiment of acetylphenylhydrazine and cyclophosphamide showed that the model group had obvious blood deficiency, and the histopathology and blood routine were effectively restored after administration. Our findings indicate that SXBM's therapeutic effect on BDS primarily involves the mediation of the HIF-1 alpha/NF- kappa B signaling pathway and the regulation of hematopoietic factor expression. Conclusion: This study not only affirmed the protective properties of SXBM against BDS but also provided insights into a potential mechanism for blood replenishment in the treatment of BDS using SXBM.

Mutant isocitrate dehydrogenase 1 (mIDH1) is a common driving factor in acute myeloid leukemia (AML), with the R132 mutation accounting for a high proportion. The U.S. Food and Drug Administration (FDA) approved Ivosidenib, a molecular entity that targets IDH1 with R132 mutations, as a promising therapeutic option for AML with mIDH1 in 2018. It was of concern that the occurrence of disease resistance or recurrence, attributed to the IDH1 R132C/S280F second site mutation, was observed in certain patients treated with Ivosidenib within the same year. Furthermore, it should be noted that most mIDH1 inhibitors demonstrated limited efficacy against mutations at this specific site. Therefore, there is an urgent need to investigate novel inhibitors targeting mIDH1 for combating resistance caused by IDH1 R132C/S280F mutations in AML. This study aimed to identify novel mIDH1 R132C/S280F inhibitors through an integrated strategy of combining virtual screening and dynamics simulations. First, 2000 hits were obtained through structure-based virtual screening of the COCONUT database, and hits with better scores than −10.67 kcal/mol were obtained through molecular docking. A total of 12 potential small molecule inhibitors were identified through pharmacophore modeling screening and Prime MM-GBSA. Dynamics simulations were used to study the binding modes between the positive drug and the first three hits and IDH1 carrying the R132C/S280F mutation. RMSD showed that the four dynamics simulation systems remained stable, and RMSF and Rg showed that the screened molecules have similar local flexibility and tightness to the positive drug. Finally, the lowest energy conformation, hydrogen bond analysis, and free energy decomposition results indicate that in the entire system the key residues LEU120, TRP124, TRP267, and VAL281 mainly contribute van der Waals forces to the interaction, while the key residues VAL276 and CYS379 mainly contribute electrostatic forces.

Carnitine palmitoyltransferase 1A (CPT1A), which resides on the mitochondrial outer membrane, serves as the rate-limiting enzyme of fatty acid beta-oxidation. Identifying the compounds targeting CPT1A warrants a promising candidate for modulating lipid metabolism. In this study, we developed a CPT1A-overexpressed mitochondrial membrane chromatography (MMC) to screen the compounds with affinity for CPT1A. Cells overexpressing CPT1A were cultured, and subsequently, their mitochondrial membrane was isolated and immobilized on amino-silica gel cross-linked by glutaraldehyde. After packing the mitochondrial membrane column, retention components of MMC were performed with LC/MS, whose analytic peaks provided structural information on compounds that might interact with mitochondrial membrane proteins. With the newly developed MMC-LC/MS approach, several Chinese traditional medicine extracts, such as Scutellariae Radix and Polygoni Cuspidati Rhizoma et Radix (PCRR), were analyzed. Five noteworthy compounds, baicalin, baicalein, wogonoside, wogonin, and resveratrol, were identified as enhancers of CPT1A enzyme activity, with resveratrol being a new agonist for CPT1A. The study suggests that MMC serves as a reliable screening system for efficiently identifying modulators targeting CPT1A from complex extracts.

OBJECTIVE:Non-small-cell lung cancer (NSCLC) is a deadly form of cancer that exhibits extensive intercellular communication which contributed to chemoradiotherapy resistance. Recent evidence suggests that arrange of key proteins are involved in lung cancer progression, including gap junction proteins (GJPs). METHODS AND RESULTS:In this study, we examined the expression patterns of GJPs in NSCLC, uncovering that both gap junction protein, beta 2 (GJB2) and gap junction protein, beta 2 (GJB3) are increased in LUAD and LUSC. We observed a correlation between the upregulation of GJB2, GJB3 in clinical samples and a worse prognosis in patients with NSCLC. By examining the mechanics, we additionally discovered that nuclear factor erythroid-2-related factor 1 (NFE2L1) had the capability to enhance the expression of connexin26 and connexin 31 in the NSCLC cell line A549. In addition, the use of metformin was discovered to cause significant downregulation of gap junction protein, betas (GJBs) by limiting the presence of NFE2L1 in the cytoplasm. CONCLUSION:This emphasizes the potential of targeting GJBs as a viable treatment approach for NSCLC patients receiving metformin.

Isocitrate dehydrogenase 1 (IDH1) is a necessary enzyme for cellular respiration in the tricarboxylic acid cycle. Mutant isocitrate dehydrogenase 1 (mIDH1) has been detected overexpressed in a variety of cancers. mIDH1 inhibitor ivosidenib (AG-120) was only approved by the Food and Drug Administration (FDA) for marketing, nevertheless, a range of resistance has been frequently reported. In this study, several mIDH1 inhibitors with the common backbone pyridin-2-one were explored using the three-dimensional structure–activity relationship (3D-QSAR), scaffold hopping, absorption, distribution, metabolism, excretion (ADME) prediction, and molecular dynamics (MD) simulations. Comparative molecular field analysis (CoMFA, R2 = 0.980, Q2 = 0.765) and comparative molecular similarity index analysis (CoMSIA, R2 = 0.997, Q2 = 0.770) were used to build 3D-QSAR models, which yielded notably decent predictive ability. A series of novel structures was designed through scaffold hopping. The predicted pIC50 values of C3, C6, and C9 were higher in the model of 3D-QSAR. Additionally, MD simulations culminated in the identification of potent mIDH1 inhibitors, exhibiting strong binding interactions, while the analyzed parameters were free energy landscape (FEL), radius of gyration (Rg), solvent accessible surface area (SASA), and polar surface area (PSA). Binding free energy demonstrated that C2 exhibited the highest binding free energy with IDH1, which was −93.25 ± 5.20 kcal/mol. This research offers theoretical guidance for the rational design of novel mIDH1 inhibitors.

Compared with single-targeted therapy, the design and synthesis of heterozygous molecules is still a significant challenge for the discovery of antitumor drugs. Quinone oxidoreductase-1 (NQO1) is a potential target for selective cancer therapy due to its overexpression in many cancer cells and its unique bioredox properties. Based on the principle of combinatorial drug design, we successfully synthesized a new hybrid molecules 13 with an indolequinone structure. We found that the synthesized compounds exhibited much higher cytotoxicity against the tested cancer cells than free drugs. Further mechanism studies confirmed that compound 13 induced cell apoptosis was achieved by regulating p53-dependent mitochondrial pathway and cell cycle arrest at the G0/G1 phase.

Abnormal fluctuations in intracellular pH may trigger dysfunction of cells and corresponding tissues, including inflammation, Alzheimer's disease, cancer, and so on. Thus, dynamic monitoring of intracellular pH values and the range of their fluctuations are of great physiological value. In this article, we have synthesized a lysosome-targeting fluorescent probe that exhibits intramolecular charge transfer (ICT) as the dominant mechanism. The probe has the advantages of excellent optical response, membrane permeability, and high resolution. In addition, the probe has good linearity over a wide pH range from 2.0 to 10.0, which can detect the pH values in real complex food samples (apple juice, peach juice, black tea, tea π, and lemon tea). Furthermore, the probe has been successfully applied in targeted imaging of lysosomes for pH changes. To sum up, the probe has capacity to be used for detecting various pH fluctuations in vitro and vivo.