This study developed an intelligent drug-loaded micelle system based on folic acid-conjugated polyglycidol (FAPG), which incorporates a reactive oxygen species (ROS) responsive fluorophore-drug conjugate (BTBP-PTX, BP). The system integrates folate receptor-α (FR-α) targeting, esterase/ROS dual-responsive drug release, and aggregation-induced emission (AIE)-based fluorescence activation for tumor-targeted delivery and imaging. Under simulated tumor microenvironment conditions (esterase-rich, high ROS levels), the system displayed dual-responsive release behavior, achieving over 80% paclitaxel (PTX) release within 24 h through esterase-catalyzed ester bond cleavage and ROS-triggered oxalate bond hydrolysis. Cellular assays demonstrated that BP@FAPG enhanced cellular uptake by approximately 2.5-fold in MDA-MB-231 cells compared to non-targeted controls BP@GAPG, along with significant cytotoxicity (IC50 = 60 nM) and deep penetration into three-dimensional tumor spheroids-effects primarily attributed to FR-α-mediated endocytosis. Furthermore, the AIE fluorophore was activated during drug release, allowing real-time fluorescence tracking of micelle localization and release dynamics.

Considering the intrinsic difficulty of accurately determining the thermodynamic data of complex impurity‐containing systems in industrial crystallization processes, this study creatively establishes a predictive correlation between infrared spectra, operating conditions, and the thermodynamics of the racemic methionine ( dl ‐methionine) crystallization system in K 2 CO 3 aqueous systems. Using principal component analysis, random forest, and Gaussian process regression architecture, a concentration prediction machine learning sub‐model was constructed, yielding a coefficient of determination of 0.988 in the test set. Subsequently, a first‐principle sub‐model combining equilibrium conditions with the electrolyte activity coefficient model was established by developing a parameter optimization program fitted experimental data to obtain a predicting error of 2.09%. The solubilization effect of carbonate salt on methionine was quantitatively characterized. The influence of temperature, pH, and carbonate component on the distribution and activity coefficients of dl ‐methionine species was thoroughly investigated. The hybrid model can better serve for the analysis of industrial dl ‐methionine crystallization processes.

Secondary nucleation critically governs crystal size distribution (CSD), yet its precise control remains challenging. Here, in situ process analytical technologies (PAT) were used to investigate the secondary nucleation of glyphosate. A method based on a defined nucleation core-interval was established to determine the average secondary nucleation rate, enabling quantitative assessment of seed size, seed loading, seed shape, cooling rate, and agitation rate. To clarify morphology effects, an additive-free approach combining isoelectric-point and cooling crystallization was developed to prepare spheroidized seeds. Under identical size conditions, spheroidized seeds markedly suppressed secondary nucleation relative to prismatic seeds, yielding larger and narrower crystals. Thus, a seed-shape factor was incorporated into the averaged secondary nucleation model, improving performance (R 2: 0.54 to 0.95; ARD: 49.94% to 18.51%) and yielding more physically consistent exponents. These results highlight seed shape as a key regulator of secondary nucleation kinetics and offer an effective pathway for tailoring CSD.

C-glycosides are crucial scaffolds in the development of carbohydrate-based drugs, owing to their favorable pharmacological properties and metabolic stability. However, the stereoselective synthesis of specific anomers under mild conditions remains a significant challenge, particularly for the β-anomer. In this study, we developed a visible-light-mediated, photocatalyst- and metal-free strategy for the stereoselective synthesis of β-alkyl C-glycosides via radical coupling. The pivot of this methodology is the utilization of bulky silyl-protected 2,3,5,6-tetrafluoropyridin-4-ylthio (SPyf) glycosyl precursors, which induce a conformational flip to the 1C4-chair form, thereby overriding the inherent bias of the radical intermediates. This operationally simple method exhibits high stereoselectivity and functional group tolerance and is particularly efficient for the synthesis of β-configured C-xylopyranosides.

Dimethylphenols serve as important intermediates in synthesizing pharmaceuticals and agrochemicals, yet traditional distillation struggles to separate their isomers due to minimal boiling point differences, and the development of melt crystallization is hampered by lacking solid-liquid equilibrium (SLE) data for some isomers. Therefore, the SLE data of both binary and ternary mixtures of 2,3-dimethylphenol (2,3-DMP), 3,5-dimethylphenol (3,5-DMP), and 3,4-dimethylphenol (3,4-DMP) were determined by using differential scanning calorimetry in this work. Additionally, crystallographic analysis was conducted to investigate the thermodynamic characteristics of these mixtures. The experimental results indicated that all the systems investigated in this research exhibited eutectic behavior. The experimentally obtained SLE data were well correlated with the Wilson and non-random two-liquid models. The excess thermodynamic functions were calculated to analyze the types and intensities of the molecular interactions occurring in the mixtures. Furthermore, this study developed a model for the correlation between the theoretical crystallization yield and the actual cooling yield and final yield in melt crystallization. This study has furnished reliable data essential for developing and optimizing the melt crystallization process of mixtures of 2,3-DMP, 3,5-DMP, and 3,4-DMP. (c) 2025 The Chemical Industry and Engineering Society of China, and Chemical Industry Press Co., Ltd. All rights are reserved, including those for text and data mining, AI training, and similar technologies.

Considering the intrinsic difficulty of accurately determining the thermodynamic data of complex impurity-containing systems in industrial crystallization processes, this study creatively establishes a predictive correlation between infrared spectra, operating conditions, and the thermodynamics of the racemic methionine (dl-methionine) crystallization system in K2CO3 aqueous systems. Using principal component analysis, random forest, and Gaussian process regression architecture, a concentration prediction machine learning sub-model was constructed, yielding a coefficient of determination of 0.988 in the test set. Subsequently, a first-principle sub-model combining equilibrium conditions with the electrolyte activity coefficient model was established by developing a parameter optimization program fitted experimental data to obtain a predicting error of 2.09%. The solubilization effect of carbonate salt on methionine was quantitatively characterized. The influence of temperature, pH, and carbonate component on the distribution and activity coefficients of dl-methionine species was thoroughly investigated. The hybrid model can better serve for the analysis of industrial dl-methionine crystallization processes.

Janus kinase 2 (JAK2) is considered an attractive target for the treatment of triple-negative breast cancer (TNBC). Herein, we discovered six JAK2 inhibitors using structure-based virtual screening and molecular docking. Among them, JNN-5 was the best compound. It indicated strong inhibitory effects on JAK2 in the nanomolar range (IC50 = 0.41 ± 0.03 nM), and high selectivity for JAK2 over JAK1 and JAK3 (selectivity index (SI) > 73.17). Moreover, molecular dynamics (MD) simulation exhibited that JNN-5 bound with high stability to JAK2 JH1. Cellular assays revealed that JNN-5 displayed strong antiproliferative activities in the TNBC cell lines (MDA-MB-468, MDA-MB-213, HCC70, MDA-MB-157). JNN-5 significantly reduced the migration of HUVECs with the dose-dependence. JNN-5 had a significant inhibitory effect on multidrug-resistant MDA-MB-231/ADR (IC50 = 0.37 ± 0.02 μM). These data demonstrate that JNN-5 may be a highly effective and selective antitumor compound for the treatment of TNBC.

The Janus membranes with asymmetric wettability can gate oil or water transport spontaneously and directionally to facilitate the liquids transport for oil/water emulsions separation without extra energy consumption, which have attracted wide attention. However, this single-functioned either oil or water removal Janus membranes can only separate one type of emulsions and cannot meet the requirements in complex environments. Herein, a bi-functional Janus mesh membrane with selective directional oil- and water-transport integration induced by direction-directed dual asymmetric wettability is demonstrated for energetic-efficient on-demand separation of oil-in-water and water-in-oil emulsion. An ingenious double single-side asymmetric modification strategy is proposed to make a homogenous mesh membrane with special Janus interface, where one surface features oleophobicity and hydrophilicity while the other shows superhydrophobicity and oleophilicity. This direction-directed wettability imbalance gives rise to the selective directional both water and oil transport property, namely, one surface directionally transports oil and block water. In contrast, the other surface suspends the oil and directionally transports water across the membrane. According to this property, this multifunctional Janus mesh membrane achieves high-performance on-demand oil-in-water and water-in-oil emulsions separation without extra energy consumption.

The SARS-CoV-2-encoded 2-E channel is critical in the viral life cycle and pathogenesis. By facilitating viral replication, it promotes the dysregulation of inflammatory pathways, leading to cytokine storm, and triggers DNA damage response (DDR), thus exacerbating disease progression. The 2-E channel, a viroporin, is a promising antiviral target. However, the lack of specific inhibitors and effective screening methods has hindered therapeutic exploitation of the 2-E channel. To address this gap, we report on a fluorescence-based screening assay that targets the 2-E channel activity, resulting in the identification of potential inhibitory molecules. After performing both electrophysiological studies and surface plasmon resonance (SPR) analyses, we identified the top-ranked candidate, TPN10518, as a pore-blocking inhibitor of the 2-E channel. TPN10518 binds to a hydrophobic pocket in the C-terminal vestibule of the 2-E channel, thereby inhibiting its activity. Functional evaluation showed that TPN10518 exhibits significant antiviral efficacy in vitro, while, at the same time, effectively protecting against 2-E channel-mediated host damage and suppressing cytokine storm caused by dysregulated homeostasis of inflammatory pathways in vivo. Therefore, our work introduces a screening method for targeting 2-E channels, establishes the 2-E channel as a viable therapeutic target against SARS-CoV-2, and identifies TPN10518 as a promising antiviral candidate.

RAD51 is involved in the homologous recombination of DNA double-strand breaks by being directed to single-stranded DNA with the assistance of the BRCA2 protein. Therefore, blocking the interaction between RAD51 and BRCA2 is considered to be a potential anticancer therapy. Currently, D-peptide inhibitors are widely recognized for their biological stability, low immunogenicity and target specificity. Here, we have identified a novel, potent and biostable D-amino acid-containing peptide inhibitor (RB-1) that blocks the RAD51-BRCA2 interaction through an integrated virtual screening protocol. MST and FP experiments showed that RB-1 had excellent binding affinity for RAD51. MD simulation confirmed the stable binding of RB-1 to the active binding site of RAD51. Furthermore, RB-1 exhibited significant antiproliferative activity on a panel of kidney cancer cell lines and less toxicity to normal cells, suggesting its potential therapeutic effects. Meanwhile, RB-1 exerted antitumor effects by inhibiting HR repair. In addition, RB-1 had good biological stability in mouse serum, highlighting its potential for in vivo activity. In vivo studies showed that RB-1 can effectively suppress tumor growth in mice without causing serious systemic side effects. In conclusion, these results suggest that D-amino acid-containing peptide RB-1 is a promising antitumor agent for kidney cancer and merits further investigation.

Perakine reductase (PR) is an aldo-keto reductase (AKR) carbonyl reductase. His126 is one of the AKR catalytic tetrads in PR. Substitution of His126 with any other amino acids except Gln switched PR to an ene reductase. Molecular simulation suggested that the substrate-binding pose and the properties of the 126 residue determined the chemoselectivity. Given the strict conservation of His126 in AKR superfamily carbonyl reductases, modification of the corresponding site is a feasible strategy to design AKR-derived novel ene reductases.

The solubility of polymorphic glycine in mixed solutions was determined, and the dissolution behavior of glycine was investigated by molecular simulation.

Surfaces exhibiting under-liquid dual superlyophobicity (combined underwater superoleophobicity and underoil superhydrophobicity) hold immense potential for intelligent oil/water separation systems, yet their realization remains thermodynamically constrained. Herein, we proposed an interfacial hydrophilic/hydrophobic chain regulation strategy that synergistically constructed an under-liquid dual superlyophobicity coating via integrating dynamic interfacial chain reorganization with multiscale structural. By programmatically regulating hydrophobic chain lengths in amphiphilic molecules, precise control over the adaptive conformational switching of self-assembled monolayers on hierarchically nanostructured substrates was achieved to tune membrane macroscopic wettability. The coating exhibits reversible wettability transitions between underoil super-hydrophobic and underwater superoleophobicity, which is consistent with the dynamic molecular reconfiguration of environment-responsive molecular chains. Consequently, the coated-porous membrane, with under-liquid dual superlyophobicity, exhibits over 99 % separation efficiency for light/heavy oil/water mixtures and emulsions, especially in long-term on-demand separation of emulsions. This practical and simple strategy provides a versatile platform for developing smart materials for on-demand treatment of complex oily wastewater.

Continuous crystallization has recently attracted extensive attention in both industry and academia. In this work, a continuous MSMPR (mixed-suspension mixed-product removal) crystallization apparatus was established, and continuous antisolvent crystallization experiments of the L-histidine-water-ethanol system were first conducted. The effects of various process parameters, such as the feed concentration, the stirring rate, and the mean residence time, on the crystal form and volume-based mean crystal size of the product were investigated. Within the explored experimental conditions, changes in the feed concentration or the stirring speed can influence the crystal size but do not affect the crystal form of the product. However, modifying the mean residence time can affect the crystalline form of the product. These findings indicate that it is possible to control the crystal form and volume-based mean size of L-histidine by adjusting the process parameters of continuous MSMPR crystallization. Finally, the continuous crystallization kinetics of form B was studied, and it was found that the growth kinetics of form B was size-dependent, and the MJ3 model was more suitable. The total nucleation and growth kinetics of form B were also fitted in this study. The results will provide some meaningful guidance on the control of polymorph and size in continuous crystallization, which is a topic of great concern in the pharmaceutical industry.

COVID-19 has caused severe consequences in terms of public health and economy worldwide since its outbreak in December 2019. SARS-CoV-2 3C-like protease (3CL(pro)), crucial for the viral replications, is an attractive target for the development of antiviral drugs. In this study, several kinds of Michael acceptor warheads were utilized to hunt for potent covalent inhibitors against 3CLpro. Meanwhile, novel 3CL(pro )inhibitors with the P3-3,5-dichloro4-(2-(dimethylamino)ethoxy)phenyl moiety were designed and synthesized which may form salt bridge with residue Glu166. Among them, two compounds 12b and 12c exhibited high inhibitory activities against SARSCoV-2 3CL(pro). Further investigations suggested that 12b with an acrylate warhead displayed potent activity against HCoV-OC43 (EC50 = 97 nM) and SARS-CoV-2 replicon (EC50 = 45 nM) and low cytotoxicity (CC50 > 10 mu M) in Huh7 cells. Taken together, this study devised two series of 3CL(pro) inhibitors and provided the potent SARS-CoV-2 3CL(pro) inhibitor (12b) which may be used for treating coronavirus infections.

In this study, the solubility of glyphosate in three binary mixed solutions (sodium chloride + water, triethylamine hydrochloride + water, and glyphosine + water) and aqueous solutions with different initial pH values was determined by a static method within the temperature range from 293.15 K to 353.15 K. Interestingly, the effects of different components on the solubility of glyphosate in aqueous solutions are quite different. The solubility of glyphosate at different initial pH shows a significant U-shaped characteristic, with the lowest solubility at about pH 1.5. In the binary mixed solutions, when the concentration of NaCl increases, the solubility of glyphosate first increases and then decreases. The increase of the triethylamine hydrochloride concentration has a negative effect on the solubility of glyphosate, while the increase of the glyphosine concentration has a positive effect on the solubility of glyphosate. The effect of pH on the solubility of glyphosate was correlated with a pH correlation model, and the solubility of glyphosate in the three mixed solutions was correlated with the modified Apelblat equation, lambda h equation, Jouyban-Acree-Apelblat (J-A-A) model and the non-randomness two-liquid (NRTL) model. The values of root mean square deviation (RMSD) indicate a good correlation of the model. In addition, the mixed thermodynamic properties (Delta mixG, Delta mixH, and Delta mixS) of glyphosate in the three binary mixed solutions were calculated based on the NRTL model, and it was found that the mixing of glyphosate in all three systems was spontaneous, heat-absorbing and entropy-driven. The obtained solubility data and thermodynamic prop-erties can provide theoretical guidance for the crystallization of glyphosate.

A series of peptidomimetic compounds containing benzothiazolyl ketone and [2.2.1] azabicyclic ring was designed, synthesized and evaluated in the hope of obtaining potent oral 3CLpro inhibitors with improved pharmacokinetic properties. Among the target compounds, 11b had the best enzymatic potency (IC50 = 0.110 μM) and 11e had the best microsomal stability (t1/2 > 120 min) and good enzyme activity (IC50 = 0.868 μM). Therefore, compounds 11b and 11e were chosen for further evaluation of pharmacokinetics in ICR mice. The results exhibited that the AUC(0-t) of 11e was 5143 h*ng/mL following single-dose oral administration of 20 mg/kg, and the F was 67.98%. Further structural modification was made to obtain compounds 11g-11j based on 11e. Among them, 11j exhibited the best enzyme inhibition activity against SARS-CoV-2 3CLpro (IC50 = 1.646 μM), the AUC(0-t) was 32473 h*ng/mL (20 mg/kg, po), and the F was 48.1%. In addition, 11j displayed significant anti-SARS-CoV-2 activity (EC50 = 0.18 μM) and low cytotoxicity (CC50 > 50 μM) in Vero E6 cells. All of the above results suggested that compound 11j was a promising lead compound in the development of oral 3CLpro inhibitors and deserved further research.

Heat shock protein 90 (Hsp90) is considered an attractive therapeutic target for cancer treatment due to its high expression in many cancers. In this study, four potent Hsp90 inhibitors (HPs 1-4) were identified using structure-based virtual screening. Among them, HP-4 exhibited the most potent inhibitory effects (IC50 = 17.64 & PLUSMN; 1.45 nM) against the Hsp90 protein, which was about 7.7 times stronger than that of MPC-3100 (a positive inhibitor targeting Hsp90). In vitro cytotoxicity assay suggested that HP-4 could effectively inhibit the proliferation of a series of tumour cells, including HCT-116, HeLa, A549, A2780, DU145, HepG2 and A498. Furthermore, in vivo assay displayed that HP-4 had significant anti-tumour effects on HCT-116 cell-derived xenograft models. These data demonstrate that HP-4 could be a potential lead compound for the further investigation of anti-tumour drugs.

In this paper, a series of peptidomimetic SARS-CoV-2 3CL protease inhibitors with new P2 and P4 positions were synthesized and evaluated. Among these compounds, 1a and 2b exhibited obvious 3CLpro inhibitory activities with IC50 of 18.06 nM and 22.42 nM, respectively. 1a and 2b also showed excellent antiviral activities against SARS-CoV-2 in vitro with EC50 of 313.0 nM and 170.2 nM, respectively, the antiviral activities of 1a and 2b were 2- and 4-fold better than that of nirmatrelvir, respectively. In vitro studies revealed that these two compounds had no significant cytotoxicity. Further metabolic stability tests and pharmacokinetic studies showed that the metabolic stability of 1a and 2b in liver microsomes was significantly improved, and 2b had similar pharmacokinetic parameters to that of nirmatrelvir in mice.

Prostate cancer (PCa) is a clinically heterogeneous disease with a progressively increasing incidence. Concurrent inhibition of coactivator-associated arginine methyltransferase 1 (CARM1) and histone deacetylase 2 (HDAC2) could potentially be a novel strategy against PCa. Herein, we identified seven compounds simultaneously targeting CARM1 and HDAC2 through structure-based virtual screening. These compounds possessed potent inhibitory activities at the nanomolar level in vitro. Among them, CH-1 was the most active inhibitor which exhibited excellent and balanced inhibitory effects against both CARM1 (IC50 = 3.71 ± 0.11 nM) and HDAC2 (IC50 = 4.07 ± 0.25 nM). MD simulations presented that CH-1 could stably bind the active pockets of CARM1 and HDAC2. Notably, CH-1 exhibited strong anti-proliferative activity against multiple prostate-related tumour cells (IC50 < 1 µM). In vivo, assessment indicated that CH-1 significantly inhibited tumour growth in a DU145 xenograft model. Collectively, CH-1 could be a promising drug candidate for PCa treatment.