Fe-N-C catalysts represent the most promising non-precious-metal catalysts for the oxygen reduction reaction (ORR), yet insufficient activity and stability prohibit their practical implementation in proton exchange membrane fuel cells (PEMFCs). Herein, we develop an ultrahigh-density FeN4 site catalyst (denoted as Fe-N-CcoCVD) coated with a thin carbon layer via a co-chemical vapor deposition (co-CVD) strategy. The Fe-N-CcoCVD catalyst achieves a site density of 2.49 & times; 1020 sites g-1 , an order of magnitude higher than that of conventional Fe-N-C catalysts. This approach generates iron nitride intermediates that bypass oxide formation to facilitate FeN4 site construction. Besides, it also deposits a protective carbon layer shielding the active sites from electrochemical degradation. Owing to these merits, the designed catalyst demonstrates exceptional activity and stability, exhibiting a half-wave potential of 0.901 V and only 24 mV decay after 50,000 cycles of stability testing. When integrated into PEMFCs, it delivers a peak power density of 722 mW cm-2 under H2-air conditions and maintains 93.2% of initial performance after 30,000 cycles of accelerated stress tests (ASTs). This work not only presents an efficient strategy for breaking the activity-stability trade-off in Fe-N-C catalysts but also provides valuable insights into the development of high-performance non-precious-metal catalysts in PEMFCs. (c) 2026 Published by Elsevier B.V. and Science Press on behalf of Science Press and Dalian Institute of Chemical Physics, Chinese Academy of Sciences.

Four polyhydroxylated dihydro-oxazines have been synthesized as competitive products of well-known nitrones from corresponding carbohydrates through efficient and practical procedures involving a five-to-seven-steps sequence in moderate overall yields (15%-35%). The key SN2 N- or O-attack ring-cyclization steps to afford the desired dihydro-oxazines were found to be significantly influenced by fluoride concentration, alkalinity, and water content in the reaction system. Reactivities of d- and l-ribose-derived polyhydroxylated dihydro-oxazines were then fully screened under reduction and nucleophilic organometallic addition conditions, revealing them as excellent synthons in affording versatile products including C-1 modified N,O-ketal, 1,2-oxazinanes, and related nitrile derivatives under different conditions. Subsequently, a compound library containing 34 polyhydroxylated 1,2-oxazinanes was established and subjected to thorough glycosidase inhibition and an anticancer study. While most of them showed no inhibition of the tested glycosidases, part of these compounds demonstrated moderate or weak inhibitory activities against the MOLT-4 cell line, providing implications for subsequent screening of related iminosugar derivatives with potential anticancer activities.

Pharmacological chaperones can enhance the stability of the three-dimensional structure by reversibly binding to the active site of mutant enzymes, thereby promoting maturation within the cell and transport to the lysosome. This study provides an example of a high-affinity ligand design strategy for lysosomal acid β-glucocerebrosidase (GCase), focusing on introducing a biphenyl substituent at the C4 position of 1,4-dideoxy-1,4-imino-D-arabinitol (DAB) in place of the native hydroxymethyl group. The introduction of a p-CF3-biphenyl group at the C4 position shifted the binding selectivity of DAB from α-glucosidase to β-glucosidase while simultaneously increasing binding affinity by 4289-fold compared to DAB, exhibiting nanomolar affinity (Ki = 0.045 μM). These findings suggest a novel possibility that contradicts the conventional view that modification of the hydroxymethyl group at the C4 position of the pyrrolidine ring inevitably leads to loss of sugar recognition ability and a consequent decrease in binding affinity. The docking models and molecular dynamics simulations showed that para-trifluoromethyl substitution restricts the mobility of the B-ring of the biphenyl moiety within the hydrophobic pocket of GCase. This interaction of the para-trifluoromethyl group and the hydrophobic pocket stabilises the active site architecture and markedly suppresses dynamic fluctuations of loop 1 and loop 2 compared with fluctuations observed in the isofagomine complex, thereby contributing to enhanced thermodynamic stabilisation of the enzyme. 4-Dehydroxymethyl-4-C-(p-CF3-biphenyl)-DAB (6e) dose dependently increased intracellular GCase activity in V394L and L444P mutant cells. It is noteworthy that the effective dose was about 10-fold lower than that for isofagomine. Therefore, 4-dehydroxymethyl-4-C-(p-CF3-biphenyl)-DAB (6e) is expected to increase intracellular mutant enzyme activity and may represent a useful therapeutic option for the treatment of Gaucher disease.

Oxidative free radical attack on FeN4 sites represents a critical degradation pathway for Fe-N-C oxygen reduction reaction (ORR) catalysts, posing a fundamental constraint on achieving both high activity and long-term durability. Motivated by this challenge, we engineer a dense surface layer of Mn single-atom sites on Fe-N-C (denoted as Fe-N-C-CVDMn) via chemical vapor deposition (CVD). The outer MnN4 sites effectively scavenge oxidizing radicals and suppress H2O2 formation, thereby markedly inhibiting demetallation of the inner FeN4 active sites and enhancing operational stability. After durability testing, Fe-N-C-CVDMn exhibits an overall metal demetallation of merely similar to 9%, which is substantially lower than that of the Fe-N-C catalyst (similar to 60%). Moreover, this MnN4/FeN4 dual-layer architecture enables improved intrinsic activity due to electronic modulation. When integrated into proton exchange membrane fuel cells (PEMFCs), it achieves power densities of 566 mW cm(-2) under H-2-air conditions and 1.13 W cm(-2) under H-2-O-2 conditions. After 30,000 cycles of accelerated stress tests (ASTs), the power density retention reaches 94%, significantly outperforming the Fe-N-C catalyst (73%). Meanwhile, it also delivers outstanding stability during a 126 h constant-voltage test. This CVD-based design establishes an efficient radical-scavenging system and provides a general strategy for simultaneously enhancing the activity and stability of M-N-C catalysts.

The weak adsorption energy of oxygen-containing intermediates on Co center leads to a considerable performance disparity between Co-N-C and costly Pt benchmark in catalyzing oxygen reduction reaction (ORR). In this work, we strategically engineer the active site structure of Co-N-C via B substitution, which is accomplished by the pyrolysis of ammonium borate. During this process, the in-situ generated NH3 gas plays a critical role in creating surface defects and boron atoms substituting nitrogen atoms in the carbon structure. The well-designed CoB1N3 active site endows Co with higher charge density and stronger adsorption energy toward oxygen species, potentially accelerating ORR kinetics. As expected, the resulting Co-B/N-C catalyst exhibited superior ORR performance over Co-N-C counterpart, with 40 mV, and fivefold enhancement in half-wave potential and turnover frequency (TOF). More importantly, the excellent ORR performance could be translated into membrane electrode assembly (MEA) in a fuel cell test, delivering an impressive peak power density of 824 mW & centerdot;cm-2, which is currently the best among Co-based catalysts under the same conditions. This work not only demonstrates an effective method for designing advanced catalysts, but also affords a highly promising non-precious metal ORR electrocatalyst for fuel cell applications.

C-2 Fluorinated castanospermines have been synthesized from a well-protected aldehyde precursor and evaluated as glycosidase inhibitors in comparison with castanospermine, 1-epi-castanospermine and C-1 fluorinated castanospermines. While C-1 fluorinated castanospermines lose nearly all the glycosidase inhibition shown by castanospermine and 1-epi-castanospermine, C-2 fluorinated derivatives of castanospermine were found to be potent and highly specific α-glucosidase inhibitors; however, the C-2 fluorinated 1-epi-castanospermines showed a sharp decrease in inhibition towards all tested enzymes. Docking calculations attributed the sharp decrease of glycosidase inhibition of C-1 fluorinated castanospermines to the disappearance of hydrogen bonds between the original C-1 hydroxyls and residues Arg-526 and Asp-327. The retained potent and specific α-glucosidase inhibition of C-2 fluorinated castanospermines was achieved by the fluorine-induced reestablishment of the docking mode in the active site; and the sharply decreased inhibition of C-2 fluorinated 1-epi-castanospermines can be attributed to obvious binding distorsion and disappearance of the hydrogen bonding with residues His-600 and Arg-526. Reliability of the docking results was evaluated by Molecular Dynamics (MD) simulation, which provided necessary calibrations to the calculation results. The interaction modes of fluorine reported herein are different from the "mimic effect" of fluorine for hydrogen, offering insights and extending our previous work on fluorinated casuarines. These results would be important for the development of castanospermine-related drug candidates for the treatment of diabetes, viral infections and Pompe disease.

Fe–N–C is hailed as the most promising candidate for replacing costly platinum-based catalysts for proton-exchange membrane fuel cells (PEMFCs) owing to their impressive catalytic activity and low cost. However, the durability of Fe–N–C catalysts remains a major challenge, primarily due to an insufficient understanding of their degradation mechanisms. In this study, we monitor the real-time changes in the electrode during the oxygen reduction reaction (ORR), shedding light on the potential-dependent degradation mechanisms inherent to Fe–N–C catalysts. Utilizing in-situ differential electrochemical mass spectroscopy, we identify three distinct potential regions with varying degrees of performance loss, notably observing carbon corrosion signals at low potentials. Theoretical calculations and fluorescence probe experiments corroborate that degradation mechanisms at high potentials are primarily driven by strong oxidative potentials that overcome the carbon oxidation energy barrier, whereas the degradation at low potentials is predominantly caused by the high concentrations of reactive oxygen species (ROS) generated during the ORR. The potential-dependent carbon corrosion consequently leads to a similar dependence of demetallation of active sites on the working potential. This study offers a comprehensive understanding of the intrinsic interrelations among various degradation mechanisms, thus paving the way for enhancing the durability of Fe–N–C catalysts in PEMFC applications.

Broussonetine S (9), its C-1' and C-10' stereoisomers, and their corresponding enantiomers have been synthesized from enantiomeric arabinose-derived cyclic nitrones, with cross metathesis (CM), epoxidation and Keck asymmetric allylation as key steps. Glycosidase inhibition assays showed that broussonetine S (9) and its C-10' epimer (10'-epi-9) were nanomolar inhibitors of bovine liver β-galactosidase and β-glucosidase; while their C-1’ stereoisomers were 10-fold less potent towards these enzymes. The glycosidase inhibition results and molecular docking calculations revealed the importance of the configurations of pyrrolidine core and C-1' hydroxyl for inhibition potency and spectra. Together with the docking calculations we previously reported for α-1-C-alkyl-DAB derivatives, we designed and synthesized a series of 6-C-alkyl-DMDP derivatives with very simple alkyl chains. The inhibition potency of these derivatives was enhanced by increasing the length of the side chain, and maintained at nanomolar scale inhibitions of bovine liver β-glucosidase and β-galactosidase after the alkyl groups are longer than eight or ten carbons for the (6R)-C-alkyl-DMDP derivatives and their 6S epimers, respectively. Molecular docking calculations indicated that each series of 6-C-alkyl-DMDP derivatives resides in the same active site of β-glucosidase or β-galactosidase with basically similar binding conformations, and their C-6 long alkyl chains extend outwards along the hydrophobic groove with similar orientations. The increasing inhibitions of β-glucosidase and β-galactosidase with the number of carbon atoms in the side chains may be explained by improved adaptability of longer alkyl chains in the hydrophobic grooves. In addition, the lower β-glucosidase and β-galactosidase inhibitions of (6S)-C-alkyl-DMDP derivatives than their C-6 R stereoisomers can be attributed to the misfolding of their alkyl chains and resulted decreased adaptability in the hydrophobic groove. The work reported herein is valuable for design and development of more potent and selective inhibitors of β-galactosidase and β-glucosidase, which have potential in treatment of lysosomal storage diseases. Furthermore, part of the 6-C-alkyl-DMDP derivatives and their enantiomers were also tested as potential anti-cancer agents; all the compounds tested were found with moderate cytotoxic effects on MKN45 cells, which would indicate potential applications of these iminosugars in development of novel anticancer agents.

Six C-6 fluorinated d-swainsonine derivatives and their enantiomers have been designed based on initial docking calculations, and synthesized from enantiomeric ribose-derived aldehydes, respectively. Glycosidase inhibition assay of these derivatives with d-swainsonine (1) and l-swainsonine (ent-1) as contrasts found that the C-6 fluorinated d-swainsonine derivatives with C-8 configurations as R (α) showed specific and potent inhibitions of jack bean α-mannosidase (model enzyme of Golgi α-mannosidase II); whereas their enantiomers with C-8 configurations as S (β) were powerful and selective α-l-rhamnosidase inhibitors. Molecular docking calculations found the C-6 fluorinatedd-swainsonine derivatives 21, 24 and 25 with highly coincident binding conformations with d-swainsonine (1) in their interactions with the active site of α-mannosidase (PDB ID: 1HWW). Reliability of the docking results were confirmed by Molecular Dynamics (MD) simulation. Additionally, solid interactions with residues Gln-392 and Tyr-393 in the active site of α-l-rhamnosidase (PDB ID: 3W5N) were proved to be vital for potent α-l-rhamnosidase inhibitions of the l-swainsonine derivatives. The role of C-6 fluorines in swainsonine derivatives well demonstrated the “mimic effect” of fluorine to hydrogen by minimal influence on the binding conformations and effective compensation for any possible lost interactions. This work contributes to a comprehensive understanding of the structure-activity relationship (SAR) of the fluorinated swainsonines and ever reported branched swainsonines, and has laid good foundation for development of more potent α-mannosidase and α-l-rhamnosidase inhibitors.

We report a strategy for stereoselective O‐aryl‐glycoside synthesis by copper‐catalyzed cross‐coupling of a variety of anomeric sugars and (hetero)aromatic iodides. Stereocontrol of the α/β selectivity can be successfully realized by slight structural modifications of the oxalic diamide ligands. Mechanistic studies indicated a dynamic kinetic resolution (DKR) reaction mechanism controlled by the ligand structures. This reaction could be performed on gram scale, and has also been applied to the synthesis of some natural products.

Prolonged activation of the type I interferon (IFN-I) pathway leads to autoimmune diseases such as systemic lupus erythematosus (SLE). Metabolic regulation of cytokine signaling is critical for cellular homeostasis. Through metabolomics analyses of IFN-β-activated macrophages and an IFN-stimulated-response-element reporter screening, we identified spermine as a metabolite brake for Janus kinase (JAK) signaling. Spermine directly bound to the FERM and SH2 domains of JAK1 to impair JAK1-cytokine receptor interaction, thus broadly suppressing JAK1 phosphorylation triggered by cytokines IFN-I, IFN-II, interleukin (IL)-2, and IL-6. Peripheral blood mononuclear cells (PBMCs) from individuals with SLE showing decreased spermine concentrations exhibited enhanced IFN-I and lupus gene signatures. Spermine treatment attenuated autoimmune pathogenesis in SLE and psoriasis mice and reduced IFN-I signaling in monocytes from individuals with SLE. We synthesized a spermine derivative (spermine derivative 1 [SD1]) and showed that it had a potent immunosuppressive function. Our findings reveal spermine as a metabolic checkpoint for cellular homeostasis and a potential immunosuppressive molecule for controlling autoimmune disease.

The reactant concentration at the catalytic interface holds the key to the activity of electrocatalytic hydrogen evolution reaction (HER), mainly referring to the capacity of adsorbing hydrogen and electron accessibility. With hydrogen adsorption free energy (Δ G H ) as a reactivity descriptor, the volcano curve based on Sabatier principle is established to evaluate the hydrogen evolution activity of catalysts. However, the role of electron as reactant received insufficient attention, especially for noble metal-free compound catalysts with poor conductivity, leading to cognitive gap between electronic conductivity and apparent catalytic activity. Herein we successfully construct a series of catalyst models with gradient conductivities by regulating molybdenum disulfide (MoS 2 ) electronic bandgap via a simple solvothermal method. We demonstrate that the conductivity of catalysts greatly affects the overall catalytic activity. We further elucidate the key role of intrinsic conductivity of catalyst towards water electrolysis, mainly concentrating on the electron transport from electrode to catalyst, the electron accumulation process at the catalyst layer, and the charge transfer progress from catalyst to reactant. Theoretical and experimental evidence demonstrates that, with the enhancement in electron accessibility at the catalytic interface, the dominant parameter governing overall HER activity gradually converts from electron accessibility to combination of electron accessibility and hydrogen adsorbing energy. Our results provide the insight from various perspective for developing noble metal-free catalysts in electrocatalysis beyond HER.

A series of DAB-peptide and DAB-dipeptide derivatives were synthesized from D-tartrate-derived nitrone 18. The DAB peptides 16 are derivatives of trans,trans-3,4-dihydroxy-L-proline. Glycosidase inhibition assay found four of them to be weak and selective bovine liver β-galactosidase inhibitors, and the C-2' methyl substituted compound 23b showed the most potent β-galactosidase inhibition (IC50 = 0.66 μM). Molecular docking studies revealed different docking modes of compound 23b compared to those of other DAB-peptides, and partial similarity of compound 23b to DGJ.

Metal-Nitrogen-Carbon (M-N-C) materials are the most promising Platinum-group-metal (PGM)-free catalysts in replacing the high-cost and scarce Pt catalysts in proton exchange membrane fuel cells (PEMFCs). However, while striking improvement of M-N-C catalysts has been reached in activity, the headache degradation problems hinder their real-world application. Herein, we present a comprehensive overview of the durability of the M-N-C catalyst for oxygen reaction reduction (ORR). The fundamental understanding and identification of the ORR performance of M-N-C catalysts are discussed. Meanwhile, the standard methods to evaluate and predict the ORR performance of the PGM-free catalysts are suggested. We mainly introduce the durability challenges of the M-N-C catalyst and explain the inactivation mechanism in detail. The proposed solution and useful strategies to alleviate catalyst degradation are systematically summarized to overcome the durability bottlenecks.

ABSTRACT Oxygen reduction reactions (ORRs) involve a multistep proton-coupled electron process accompanied by the conversion of the apodictic spin configuration. Understanding the role of spin configurations of metals in the adsorption and desorption of oxygen intermediates during ORRs is critical for the design of efficient ORR catalysts. Herein, a platinum–rare-earth-metal-based alloy catalyst, Pt2Gd, is introduced to reveal the role of spin configurations in the catalytic activity of materials. The catalyst exhibits a unique intrinsic spin reconfiguration because of interactions between the Gd-4f and Pt-5d orbitals. The adsorption and desorption of the oxygen species are optimized by modifying the spin symmetry and electronic structures of the material for increased ORR efficiency. The Pt2Gd alloy exhibits a half-wave potential of 0.95 V and a superior mass activity of 1.5 A·mgPt−1 in a 0.1 M HClO4 electrolyte, as well as higher durability than conventional Pt/C catalysts. Theoretical calculations have proven that the spin shielding effect of Gd pairs increases the spin symmetry of Pt-5d orbitals and adsorption preferences toward spin-polarized intermediates to facilitate ORR. This work clarifies the impact of modulating the intrinsic spin state of Pt through the interaction with the local high spin 4f orbital electrons in rare-earth metals, with the aim of boosting the spin-related oxygen reduction reaction, thus fundamentally contributing to the understanding of new descriptors that control ORR activity.

A series of iso-allo-DNJ and L-isoDALDP derivatives were synthesized from dithioacetal 16 with sequential and highly diastereoselective Ho and Henry reactions, and aziridinium intermediate-mediated ring rearrangement as key steps. Glycosidase inhibition assay found four of them as selective α-glucosidase inhibitors, and the less substituted compound 30 showed more potent α-glucosidase inhibition (IC50 = 9.3 μM) than the others. Molecular docking study revealed different docking modes of the iso-allo-DNJ and L-isoDALDP derivatives from their parent compounds, and also the similarity of compound 30 to isofagomine.

Metal-nitrogen-carbon materials are the most promising platinum replacement catalysts for oxygen reduction reaction. However, lacking an efficient approach to improve durability—i.e., to cope with the attack by in situ formed radicals, leaching of central ions, etc.—has limited these catalysts from widespread application. Herein we present a novel, dual-metal, single-atom catalyst design (Fe,Ce-N-C) to confront the formidable deactivation issue of the best-performing yet unstable Fe-N-C catalysts. Cerium single sites are revealed as efficient chemical catalysts to catalyze the H2O2 disproportionation into O2, leading to increased 4e selectivity. Moreover, rather than Fe single sites that catalyze the formation of reactive ·OH and ·OOH species, these cerium single sites act proactively to eliminate in situ-generated radicals. The final Fe,Ce-N-C catalyst represents excellent durability exceeding that of Fe-N-C. This work opens a new path to alleviate the degradation of Fe-N-C catalysts in an acidic medium.

Proton-exchange membrane fuel cells (PEMFCs) are an efficient and clean energy conversion technology with the advantage of zero pollution for transportation applications. The oxygen reduction reaction (ORR) is the key step in the energy conversion at the cathode, but the slow kinetics requires a high content of expensive platinum-group -metal (PGM) catalysts. Therefore, research on high-performance and inexpensive catalysts to replace PGM-based catalysts are essential to promote the commercialization of fuel cells. Single-atom catalysts (SACs) with highly active sites that are atomically dispersed on substrates exhibit unique advantages, such as maximum atomic utilization, abundant chemical structures, and extraordinary catalytic performances for multiple important reactions. Inspired by macrocyclic compounds with MN4 active centers, the application of pyrolyzed M-NX/C type SACs (M = Fe, Co, Mn, Ru, Cr, Zn, etc.) in the ORR has significantly progressed within the last ten years. Particularly, single-atom Fe-N-C catalysts have been extensively investigated, demonstrating high ORR activity, which indicates that the initial electrochemistry and fuel cell performance are similar to that of conventional Pt/C catalysts. However, in the oxidizing and acidic PEMFC cathode, Fe-N-C catalysts are degraded rapidly, which hinders the application of these nonprecious metal M-NX/C-type catalysts. Several degradation mechanisms have been proposed over the past few years, such as carbon oxidation, demetallation, and waterflooding. However, the degradation mechanisms remain unknown and require further investigation of the underlying causes of the mechanism, degradation process, and coping strategies. To achieve the future commercialization of high-performance M-NX/C catalysts, several key challenges are summarized with potential research guidelines proposed to overcome bottlenecks. This review summarizes the development history and state-of-the-art research progress on nonprecious metal M-NX/C-type catalysts in PEMFCs. First, we introduce the basic theory of the ORR and the methods of advanced characterization techniques for active site identification and reaction mechanism analysis to gain a comprehensive understanding of the structure-performance relationship. Subsequently, the representative studies and recent advancements in M-NX/C-type catalysts by experimental and theoretical calculations are presented. Additionally, we analyze the root cause of the stability problems and propose the corresponding solution strategies to promote the intrinsic electrocatalytic ORR activity and durability, including regulating the electronic structure and coordination environment, as well as altering the central metal atoms and guest groups. Finally, we propose that the future direction of M-NX/C-type catalysts is the rational design of catalysts with a high site density and high stability. Moreover, improving the lifetime of nonprecious metal catalysts remains essential for feasible applications in the future.

Inspired by Roush's pioneering work on rare sugars, we have developed a scalable, stereoselective, de novo synthesis of orthogonally protected C2-fluoro digitoxose and cymarose, utilizing Sharpless kinetic resolution and organocatalytic fluorination as key steps. The utility of this strategy is demonstrated by the synthesis of a fluorinated analogue of digoxin, which indicates the fluorine on the sugar ring may have a significant impact on biological activity.

In recent years, the function of pharmacological chaperones as a "thermodynamic stabilizer" has been attracting attention in combination therapy. The coadministration of a pharmacological chaperone and recombinant human acid α-glucosidase (rhGAA) leads to improved stability and maturation by binding to the folded state of the rhGAA and thereby promotes enzyme delivery. This study provides the first example of a strategy to design a high-affinity ligand toward lysosomal acid α-glucosidase (GAA) focusing on alkyl branches on 1-deoxynojirimycin (DNJ); 5-C-heptyl-DNJ produced a nanomolar affinity for GAA with a Ki value of 0.0047 μM, which is 13-fold more potent than DNJ. The protein thermal shift assay revealed that 10 μM 5-C-heptyl-DNJ increased the midpoint of the protein denaturation temperature (Tm) to 73.6 °C from 58.6 °C in the absence of the ligand, significantly improving the thermal stability of rhGAA. Furthermore, 5-C-heptyl-DNJ dose dependency increased intracellular GAA activities in Pompe patient's fibroblasts with the M519V mutation. The introduction of C5 alkyl branches on DNJ provides a new molecular strategy for pharmacological chaperone therapy for Pompe disease, which may lead to the development of higher-affinity and practically useful chaperones.