Latest ArticlesFunctionalized C−N atropisomers has become more and more attractive and found wide applications in natural products, drug molecules, as well as in chiral ligands. As a complement to asymmetric de novo ring formation and cross C−N coupling methods, the resolution approach demonstrates uniquely advantageous, which can progressively introduce the key functional groups and generate enantiomeric excess. Herein, we have developed an enzymatic tool for the construction of difunctionalized C−N atropisomers via lipase-catalyzed desymmetrization and kinetic resolution of N-naphthol-carbazoles. Acetylacetone was found as an efficient proton donor under the catalysis of LPL311-polyester. The enantioselective deacylation process has exhibited good functional group tolerance to produce enantioenriched C−N atropisomers with good to excellent enantioselectivity, in which the pre-installed hydroxyl functionality on the naphthene ring and the hydroxyl functionality on the carbazole ring generated after hydrolysis together provide feasibility for subsequent transformations.
The pathological protein α-synuclein (α-Syn) aggregates are considered a key toxic substance responsible for the degeneration of dopaminergic neurons in Parkinson's disease (PD). Clearing these pathological aggregates can potentially control PD progression at its source. However, conventional drug delivery systems face significant challenges, including the blood-brain barrier (BBB) and lack of tissue-specific targeting. To address this, we developed a core-shell hybrid system, named RExo-si-TN-T10, for the co-delivery of triptolide (T10) and small interfering RNA targeting α-Syn (siSNCA). This system comprises two components: an outer shell of exosomes (RExo) derived from BV2 microglial cells and modified with rabies virus glycoprotein peptide (RVG), and an inner core of a nanomicelle composed of phenylboronic acid derivatives: 4-Nitrophenyl 4-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) benzyl carbonate (NBC) and trimethyl chitosan (TMC) for co-delivering gene and small-molecule drugs. Furthermore, we utilized cellular nanoporation (CNP) technology to significantly enhance exosome yield and transfection efficiency. This innovative nano-scavenger effectively eliminates α-Syn aggregates and reduces their cytotoxic effects in PD-affected neurons. Following treatment with RExo-si-TN-T10, we observed significant improvement in the motor behavior of PD mice. Our findings suggest that RExo-si-TN-T10 holds promise as a therapeutic platform for PD.
The fentanyl (Fen) analogs-related drug crisis is a global focus that has badly affected social stability. In view of multitudinous overdose deaths, there is a great need for a portable and sensitive analytical approach that can quickly discriminate these dangerous recreational substances. Herein, an extended biphenarene-based fluorescence displacement sensor assay was constructed by integrating two reporter pairs, where terphen[3]arene sulfate and quaterphen[3]arene sulfate act as receptors, and rhodamine 123 acts as the optimal indicator. The formed supramolecular assay was able to completely classify four analogs, including Fen, 3-methylfentanyl, sufentanil and remifentanil in aqueous phosphate buffered saline, artificial urine, mouse plasma, or even real urine sample from model mice. Moreover, mixed samples containing different proportions of cocaine, heroin and ketamine could also be discriminated with 100% accuracy.
In this paper, a novel multicolor-responsive fluorescent probe for the rapid and sensitive detection of persulfate ions (S2O82-), KT@Q[8], is constructed via host-guest interactions between cucurbit[8]uril (Q[8]) and 3,6-bis[4-(4-bromophenyl)pyridinium]-carbazole dichloride (KT). Upon interaction with S2O82-, the KT@Q[8] probe exhibits a fluorescence emission blue shift concurrent with a fluorescence color transition gradually from yellow to green. Notably, the probe demonstrates high selectivity for S2O82- even in the presence of competing anions and sulphur-containing metal salts, achieving a detection limit of 0.38 μmol/L. When integrated with smartphone-based RGB analysis, this probe enables rapid visual quantification of S2O82- without requiring sophisticated instrumentation, and can be effectively used to detect S2O82- in tap water, lake water, honey, and white wine. Furthermore, machine learning algorithms enhanced predictive accuracy during data analysis. Overall, this work not only advances a practical approach for persulfate monitoring but also expands the application range of cucurbituril-based fluorescence supramolecular assemblies.
Herein, we report morphology and luminescence tunable supramolecule containing tetracation 6-bromoisoquinoline modified tetraphenylbenzene (TQ), cucurbit[8]uril (CB[8]), β-cyclodextrin grafted hyaluronic acid (HACD), and two dyes (SR101, Cy5), which can lead to cascade efficient phosphorescence resonance energy transfer (PRET) through multi-scale supramolecular space confinement to achieve longlived multi-wavelength emission, especially near-infrared (NIR) luminescence. The initial unit TQ was assembled to form a green phosphorescent 3D supramolecular organic framework (SOF) under the activation of CB[8] confinement and then co-assembled with polysaccharide HACD to form phosphorescence extended long-lifetime (670.3 μs) 3D nanoparticles. This hierarchical confinement boosted phosphorescence supramolecule can act as the donor to achieve efficient energy transfer from phosphor to the dye SR101, giving long-lived luminescence at 615 nm, which can be employed as a transit depot and further encapsulate secondary acceptor Cy5, achieving efficient delayed NIR fluorescence at 680 nm, and was used as phosphorescence logic gate and NIR imaging reagent.
Balsalazide disodium is an effective drug for alleviating ulcerative colitis. It slowly releases 5-aminosalicylic acid in the intestine. The traditional synthesis methods of balsalazide disodium exhibit high risk, high pollution and low efficiency concern. Thus, we innovatively develop a four-step route for the large-scale production of balsalazide disodium in continuous flow. In this work, methyl 3-aminopropionate hydrochloride was subjected to acylation and hydrolysis reactions to obtain the nitro intermediate with a selectivity of 99.55%. Micro-hydrogenation reactor filled with Raney Ni catalyzed three-phase reaction improves conversion and selectivity. In the diazotization and azo coupling reactions, the optimal equivalents of salicylic acid and base were determined. With the aid of response surface methodology, the influences of reaction temperature and residence time on yield were systematically investigated. Under the optimum conditions, the experimental yields coincided with the predicted yields. Compared to batch experiments, the continuous process achieved a total yield of 66.1% and a purity of 99.63% in 13.1 min.
Efficient macrocycle synthesis remains a persistently pursued objective in supramolecular chemistry. In this work, a series of chiral macrocycles (TBCHMs) incorporating Tröger's base were synthesized via imine condensation reactions from Tröger's base (TB) aldehyde derivatives and cyclohexane-1,2-diamines (CHDA). Gram-scale quantities of crystalline macrocycles were directly obtained during the process of their reaction. Precise modulation of macrocycle structural morphology was achieved by varying the chiral configuration of the components. Notably, chiral self-sorting was realized in these reaction systems, driven by the energy difference between diastereomers and their selective precipitation as crystals. This work might open up new insights for the modular preparation of chiral macrocycles based on dynamic covalent chemistry (DCC).
Multi-resonance thermally activated delayed fluorescence (MR-TADF) materials have attracted growing interest for their potential to achieve high color purity and efficiency in organic light-emitting diode (OLED) applications. However, their key performance parameters, including photoluminescence wavelength (PL), full width at half-maximum (FWHM), and photoluminescence quantum yield (PLQY), are highly structure-dependent, presenting challenges for high-throughput screening and efficient design. In this work, we propose a structure-aware ensemble learning model (BNML) that integrates molecular access system (MACCS) fingerprints, fingerprint2 (FP2) fingerprints, and molecular descriptors (MDs) to predict photophysical properties of MR-TADF materials. The model shows strong regression performance under small-data (415) conditions and achieves nearly 100% prediction accuracy (100%, 100%, and 96%, respectively) within a specific range of values. By incorporating SHapley Additive exPlanations (SHAP) analysis, the model reveals interpretable contributions of donor fragments and π-conjugation to the predicted properties. Guided by this analysis, fifteen novel MR-TADF compounds were designed, among which seven were successfully synthesized and validated, showing strong agreement with the predicted values (accuracy: predict/true, 21/20). This work provides a reliable strategy for intelligent design and rapid evaluation of MR-TADF compounds, offering a new approach for structure-property modeling in complex emission systems.
Multi-substituted pyrrolidine and piperidine N-heterocycles are the top scaffolds of clinical drugs, but syntheses of these scaffolds are far from trivial. Herein, we report a highly enantioselective protocol for the synthesis of 5- and 6-membered cyclic nitrones via Pd-catalyzed cyclization coupling of alkenyl oximes with aryl, alkenyl and alkynyl (pseudo)halides enabled by chiral sulfonamidephosphine (SadPhos) ligands. These cyclic nitrones products, besides their significance per ser, can be facilely converted to multi-substituted pyrrolidines and piperidines by simple operations. This study also represents the first example of two-component catalytic asymmetric synthesis of cyclic nitrones and provides important insights for further development of enantioselective heterocyclization reaction and processes involving multiple selectivity issues.
Bergenin (BG), a bioactive coumarin derivative, suffers from poor solubility and low oral bioavailability, restricting its clinical potential. To overcome these limitations, we developed a lipid prodrug strategy by conjugating BG with bioactive fatty acids of different chain lengths (6C, 12C, 18C) via ester bonds, formulating the conjugates into solid lipid nanoparticles (SLNs), and systematically investigating the structure–activity relationship. Fatty acid conjugation not only enhanced lipophilicity, lipid matrix compatibility, and enzymatic stability but also imparted distinct biological effects that shaped oral absorption. Stearic acids (18C) conferred strong resistance to enzymatic hydrolysis, whereas lauric acid (12C) offered the most favorable balance in improving drug loading, stability, and membrane permeability. Pharmacokinetic studies in rats demonstrated that 12C-BG SLNs achieved the greatest enhancement in oral bioavailability, with an 8.6-fold increase over BG-SLNs and more than 40-fold improvement relative to reported suspensions and phospholipid solid dispersions. Mechanistic studies indicated that absorption was primarily driven by prodrug monomers released during intestinal lipolysis, with a minor contribution from undigested nanoparticles, and moreover the fatty acid chain length strongly influenced cellular permeability and systemic exposure. Collectively, these results underscore the critical role of bioactive fatty acids as conjugating groups in modulating prodrug fate and highlight a promising platform for enhancing the oral delivery of poorly soluble phytochemicals.
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