Communications Chemistry最新文献

Polydiacetylene (PDA)-based colorimetric sensors offer a promising platform for rapid and visual detection, through a chromatic transition from blue to red. However, their broader applications are hindered by challenges in sensitivity, selectivity, and stability. This review comprehensively overviews functionalization strategies to overcome existing limitations, including chemical modification with reactive groups, conjugation with specific ligands or receptors, and integration with nanomaterials. Alternative approaches are also discussed. The interplay between base materials, deposition methods, and functionalization efficiencies is emphasized. Furthermore, this review addresses remaining challenges, proposes feasible solutions, and offers insights into future strategic directions for creating more advanced PDA-based colorimetric sensors.

Sample consumption for serial femtosecond crystallography with X-ray free electron lasers remains a major limitation preventing broader use in macromolecular crystallography. This drawback is exacerbated in time-resolved (TR) experiments, where the amount of sample required per reaction time point is multiplied by the number of time points investigated. To reduce this limitation, we demonstrate a segmented droplet generation strategy coupled to a mix-and-inject approach for TR studies at the European XFEL. The injector produces synchronized droplet trains that enable stable and reproducible injection of protein crystal slurries at significantly reduced flow rates. Using the human flavoenzyme NAD(P)H:quinone oxidoreductase 1 (NQO1) as a test system, we collected diffraction data after mixing with NADH at 0.3 s and 1.2 s delays. The segmented injection approach achieved up to 97% reduction in sample consumption compared with continuous-flow injection while maintaining data quality suitable for TR crystallography. Reproducible electron density features consistent with low-occupancy NADH binding illustrate both the feasibility and the current limits of studying dynamic redox enzymes using this approach. This work establishes segmented droplet generation as a sample-efficient and XFEL-compatible method for future time-resolved serial crystallography experiments.

Heterobifunctional small degrader molecules that hijack endogenous E3 ubiquitin ligases have attracted attention for the rapid and irreversible knock-down of target proteins via ubiquitination. However, the formation of appropriately oriented E3 ligase-target complexes is required for efficient ubiquitination of the target, which complicates the molecular optimization and leads to acquired drug resistance caused by the loss of E3 ligase activity and mutations at the E3-target interfaces. Here, we report on indirect ubiquitination as a chemical strategy for E3-indepedent ubiquitin-tethering to the target substrate. Comprising a ligand molecule and a ubiquitin moiety, the designed chimeric molecule enables the ubiquitination of the target proteins via non-covalent interactions, which lead to the proteasomal degradation of recombinant Bcl-2 and NF-κB p50, and intracellular endogenous Bcl-2. Indirect ubiquitination offers a design platform for non-covalent tethering of a ubiquitin-based proteolytic modifier to be added in the molecular toolbox for the targeted protein degradation.

Serine proteases in ribosomally synthesized and post-translationally modified peptides (RiPPs) catalyze the cleavage on the precursor peptides in the biosynthesis of RiPP natural products. Here, we identified an uncharacterized serine protease WprP₂ from Streptomyces venezuelae NPDC049867, encoded next to the radical S-adenosyl-L-methionine (SAM) enzyme WprB₂ involved in the biosynthesis of cyclophane natural products. In vitro characterization of S9 protease WprP₂ revealed that the precursor peptide WprA₂ is uniformly cleaved. The cleavage activity of WprP₂ has not been seen in any serine proteases and expands the S9 protease in RiPP biosynthesis.

Potency (IC₅₀) prediction of small molecules is pivotal for anticancer drug development. This study benchmarked five deep learning (DL) models for IC₅₀ prediction-DeepCDR, DrugCell, PaccMann, Precily, and tCNN-against a simple mean-based Baseline using standardized GDSC datasets and recently published anticancer compounds. To ensure practicality, conventional error metrics were supplemented with percentage error, log error, three-sigma limit, and a newly proposed Experimental Variability-Aware Prediction Accuracy statistic. The models performed well on randomly split data and unseen cell lines but showed sharply reduced accuracy for unseen compounds. Though all DL models exhibited similar performance trends, DeepCDR, DrugCell, and tCNN held a slight edge in most testing scenarios. Interestingly, several DL algorithms could not significantly outperform the Baseline model in many tests. Assessing prediction error against physicochemical and biological properties of compounds and cell lines revealed weak correlation, highlighting an underexplored aspect of model performance. A user-friendly web server (https://nlplab1.isical.ac.in/ic50.php) was also developed for IC₅₀ prediction of new compounds against cancer cell lines.

Protein conformational changes drive signal transduction to regulate cellular activities, yet monitoring of these changes in living cells remains challenging. Here, we introduce BIOSCE (BIOprobe based on Steric Confinement-induced Emission), a technique that enables tracking of individual protein conformations in living cells across millisecond-to-minute timescales. BIOSCE reports protein conformational changes via steric confinement-induced luminescence switching from non-luminescent to luminescent states. We demonstrate that BIOSCE rapidly senses calmodulin conformational changes triggered by intracellular calcium fluctuations. The BIOSCE platform achieved millisecond-resolution monitoring of single-protein conformations within cellular signaling pathways, as evidenced by its sensitive detection of rapamycin-dependent FKBP (FK506-binding protein)-FRB (FKBP-rapamycin binding) interactions regardless of the labeled partner. Furthermore, we applied BIOSCE to track the spatial distribution of SNAP25 (25 kDa synaptosomal nerve-associated protein) during botulinum neurotoxin A (BoNT/A) intoxication, revealing differential catalytic processing of its cleavage fragments. This generalizable approach provides a robust platform for investigating single-molecule conformational changes with high spatiotemporal resolution and enables direct evaluation of transient cellular events.

Deuterated alcohols are valuable synthetic targets due to their roles in pharmaceuticals, materials, and mechanistic studies. Conventional homogeneous strategies for their synthesis, while effective, often require expensive ligands and offer limited catalyst recovery. Heterogeneous catalysis, by contrast, provides a robust and recyclable alternative with enhanced scalability. Recent advances in supported metal nanoparticles and single-atom catalysts (SACs) have enabled high-efficiency and site-selective deuteration of alcohols. This Perspective presents heterogeneous catalytic systems as evolving into scalable and efficient platforms for deuterated alcohol synthesis, opening new directions for sustainable isotope incorporation.

In pursuit of the reductive conversion of NO in organic synthesis, this study presents the direct diazotization of indoles using 2-methoxyethyl nitrite (MOE-ONO). Diazo compounds are invaluable intermediates in organic synthesis, serving as carbene precursors for constructing diverse carbon frameworks. However, traditional C-H diazotization methods often require azide compounds or excessive amounts of acid/base, posing significant environmental and safety challenges. Herein, we introduce a sustainable and efficient diazotization protocol that overcomes these problems. The use of 2-methoxyethyl nitrite (MOE-ONO), a stable and highly reactive NO donor developed by our group, in combination with TEMPO and a catalytic amount of Sc(OTf)₃, played a significant role in the direct diazotization of 2-substituted indoles. MOE-ONO showed higher reactivity and selectivity than conventional NO donors, even including tert-butyl nitrite or NaNO₂/AcOH. Since MOE-ONO is synthesized from NO gas, oxygen, and 2-methoxyethanol, this diazotization serves as an effective utilization of NO. Furthermore, the diazotization proceeds efficiently even in water, which is important for designing clean chemical processes. The synthesized 3-diazoindoles exhibit broad reactivity, such as Grignard reaction at the C2-position and rhodium-catalyzed cyclopropanation at the C3-position. Such reactions can be practical solutions for synthesizing highly functionalized indoles and indolines, which are important for the design and discovery of pharmacologically active compounds.

Remote boronate rearrangement of boronic acids to C═N bonds is a valuable in synthetic chemistry. Conventional approaches are constrained by the need to pre-install specialized directing groups onto the starting materials. Here, we report a lactam-driven dynamic directing strategy, achieving 1,5- and 1,4-boronate rearrangements. The strategy circumvents the need for substrate pre-activation procedures, successfully overcoming a challenge in the functionalization of inactive C = N bonds to N-alkyl anilines and 3-aryl quinoxalinones. Comprehensive mechanistic investigations unveil three transformative insights: (i) Lactam leverages boron activation to C = N bonds through tetracoordinate boron species; (ii) the 1,5-boronate rearrangement to N-alkyl anilines is favored via an eight-membered boronate complex, as supported by density functional theory (DFT) studies; (iii) a catalyst-free 1,4-boronate rearrangement pathway operates through HFIP-stabilized tetracoordinate boron intermediates. This lactam-enabled boronate rearrangements offers a methodology with transformative potential.

Structural characterization of powder materials, including those synthesized by mechanochemical methods, remains challenging due to the lack of single crystals suitable for X-ray diffraction. Microcrystal-Electron Diffraction (MicroED) enables structure determination from sub-micrometer crystallites but faces limitations, particularly in locating hydrogen atoms and distinguishing light atoms (C, N, O). We present a general workflow that integrates MicroED with high-resolution mass spectrometry, database mining, solution and solid-state NMR, and DFT-D/GIPAW calculations to resolve atomic structures of complex powders, even with unknown composition. The approach is demonstrated on a pyridoxine-N-acetyl-L-cysteine salt, a mechanochemically synthesized adduct for which large single crystals could not be obtained, and on N-formyl-methionyl-leucyl-phenylalanine (fMLF), a bacterial chemoattractant peptide. This strategy enables comprehensive structure resolution, including identification of molecular components, crystal packing, atom assignments and hydrogen positions. Its modularity and scalability make it suitable for a wide range of powder materials, e.g., pigments, pharmaceutical compounds, etc., especially when conventional crystallography fails.