Deep learning-assisted mass spectrometry imaging for preliminary screening and pre-classification of psychoactive substances.

Currently, it is of great urgency to develop a rapid pre-classification and screening method for suspected drugs as the constantly springing up of new psychoactive substances. In most researches, psychoactive substances classification approaches depended on the similar chemical structures and pharmacological action with known drugs. Such approaches could not face the complicated circumstance of emerging new psychoactive substances. Herein, mass spectrometry imaging and convolutional neural networks (CNN) were used for preliminary screening and pre-classification of suspected psychoactive substances. Mass spectrometry imaging was performed simultaneously on two brain slices as one was from blank group and another one was from psychoactive substance-induced group. Then, fused neurotransmitter variation mass spectrometry images (Nv-MSIs) reflecting the difference of neurotransmitters between two slices were achieved through two homemade programs. A CNN model was developed to classify the Nv-MSIs. Compared with traditional classification methods, CNN achieved better estimation accuracy and required minimal data preprocessing. Also, the specific region on Nv-MSIs and weight of each neurotransmitter that affected the classification most could be unraveled by CNN. Finally, the method was successfully applied to assist the identification of a new psychoactive substance seized recently. This sample was identified as cannabinoids, which greatly promoted the screening process.

Synthesis of S(IV)-Stereogenic Chiral Thio-Oxazolidinones via Palladium-Catalyzed Asymmetric [3+2] Annulations.

Organic molecules bearing chiral sulfur stereocenters exert a great impact on asymmetric catalysis and synthesis, chiral drugs, and chiral materials. Compared with acyclic ones, the catalytic asymmetric synthesis of thio-heterocycles has largely lagged behind due to the lack of efficient synthetic strategies. Here we establish the first modular platform to access chiral thio-oxazolidinones via Pd-catalyzed asymmetric [3+2] annulations of vinylethylene carbonates with sulfinylanilines. This protocol is featured by readily available starting materials, and high enantio- and diastereoselectivity. In particular, an unusual effect of a non-chiral supporting ligand on the diastereoselectivity was observed. Possible reaction mechanisms and stereocontrol models were proposed.

AuNPs/CNC Nanocomposite with A "Dual Dispersion" Effect for LDI-TOF MS Analysis of Intact Proteins in NSCLC Serum Exosomes.

Detecting exosomal markers using laser desorption/ionization time-of-flight mass spectrometry (LDI-TOF MS) is a novel approach for examining liquid biopsies of non-small cell lung cancer (NSCLC) samples. However, LDI-TOF MS is limited by low sensitivity and poor reproducibility when analyzing intact proteins directly. In this report, gold nanoparticles/cellulose nanocrystals (AuNPs/CNC) is introduced as the matrix for direct analysis of intact proteins in NSCLC serum exosomes. AuNPs/CNC with "dual dispersion" effects dispersed and stabilized AuNPs and improved ion inhibition effects caused by protein aggregation. These features increased the signal-to-noise ratio of [M+H]+ peaks by two orders of magnitude and lowered the detection limit of intact proteins to 0.01 mg mL-1. The coefficient of variation with or without AuNPs/CNC is measured as 10.2% and 32.5%, respectively. The excellent reproducibility yielded a linear relationship (y = 15.41x - 7.983, R2 = 0.989) over the protein concentration range of 0.01 to 20 mg mL-1. Finally, AuNPs/CNC-assisted LDI-TOF MS provides clinically relevant fingerprint information of exosomal proteins in NSCLC serum, and characteristic proteins S100 calcium-binding protein A10, Urokinase plasminogen activator surface receptor, Plasma protease C1 inhibitor, Tyrosine-protein kinase Fgr and Mannose-binding lectin associated serine protease 2 represented excellent predictive biomarkers of NSCLC risk.

Intramolecular Ring-Chain Equilibrium Elimination Strategy for Pinpointing C═C Positional and Geometric Isomers of N-Alkylpyridinium Unsaturated Fatty Acid Derivatives via Ion Mobility-Mass Spectrometry.

Free unsaturated fatty acids (UFA) are key intermediates of lipid metabolism and participate in many metabolic pathways with specific biological functions. Although various fragmentation-based methods for pinpointing C═C locations in UFA were developed, the current mass spectrometry methods are difficult to simultaneously differentiate geometric isomers and positional isomers in trace samples due to low ionization efficiency, low conversion, and low resolution. Herein, an intramolecular ring-chain equilibrium elimination strategy via 4-plex stable isotope labeling dual derivatization-assisted ion mobility-mass spectrometry was developed, thereby one-pot specifically labeling C═C and carboxyl groups among the trace and unstable UFA with high sensitivity, high efficiency, and good substrate generality. It achieved fast separation of both C═C positional and geometric isomers with high resolution, which benefited from eliminating the intramolecular ring-chain equilibrium by suppressing the formation of salt bridges between free carboxyl groups and pyridine cations. 4-plex stable isotope labeling reagents showed similar reactivity, enabling high-throughput quantitative analysis of omics. This method was successfully applied for accurate and rapid identification of the UFA composition in olive oil extract. These results suggest that the developed method provides new insight for rapid characterization of UFA C═C positional and geometric isomers in complex samples to explore disease biomarkers and food quality control indicators.

Iridium-Catalyzed Enantioselective Transfer Hydrogenation of 1,1-Dialkylethenes with Ethanol: Scope and Mechanism.

Despite half a century's advance in the field of transition-metal-catalyzed asymmetric alkene hydrogenation, the enantioselective hydrogenation of purely alkyl-substituted 1,1-dialkylethenes has remained an unmet challenge. Herein, we describe a chiral PCNOx-pincer iridium complex for asymmetric transfer hydrogenation of this alkene class with ethanol, furnishing all-alkyl-substituted tertiary stereocenters. High levels of enantioselectivity can be achieved in the reactions of substrates with secondary/primary and primary/primary alkyl combinations. The catalyst is further applied to the redox isomerization of disubstituted alkenols, producing a tertiary stereocenter remote to the resulting carbonyl group. Mechanistic studies reveal a dihydride species, (PCNOx)Ir(H)2, as the catalytically active intermediate, which can decay to a dimeric species (κ3-PCNOx)IrH(µ-H)2IrH(κ2-PCNOx) via a ligand-remetalation pathway. The catalyst deactivation under the hydrogenation conditions with H2 is much faster than that under the transfer hydrogenation conditions with EtOH, which explains why the (PCNOx)Ir catalyst is effective for the transfer hydrogenation but ineffective for the hydrogenation. The suppression of di-to-trisubstituted alkene isomerization by regioselective 1,2-insertion is partly responsible for the success of this system, underscoring the critical role played by the pincer ligand in enantioselective transfer hydrogenation of 1,1-dialkylethenes. Moreover, computational studies elucidate the significant influence of the London dispersion interaction between the ligand and the substrate on enantioselectivity control, as illustrated by the complete reversal of stereochemistry through cyclohexyl-to-cyclopropyl group substitution in the alkene substrates.

Inhibiting Protein Aggregation Using Cellulose Nanocrystal in MALDI-TOF MS Analysis: Improving the Sensitivity and Repeatability of Intact Protein in Pueraria.

Protein aggregation can induce low sensitivity and poor repeatability of matrix-assisted laser desorption/ionization time-of-fight mass spectrometry (MALDI-TOF MS) analysis for intact protein. Herein, we introduced a strategy to decrease protein aggregation in the sample solution by using cellulose nanocrystal (CNC). The results indicated that protein granule size was effectively reduced by adding CNC to the sample solution. Through MALDI-TOF MS analysis, the signal-to-noise ratio of [M + H]+ peak increased 2-fold, and the detection of limit was <10 µg/mL for intact protein. The CNC also contributed to excellent point-to-point repeatability for MALDI-TOF MS analysis with the coefficient of variation (CV) of 10.0% with CNC vs 48.9% without CNC in Hb solution. Also, the repeatability of Pueraria protein ion signals was improved by using CNC, and the CV with and without CNC was 16.1% and 39.6%, respectively. Moreover, protein ion intensity exhibited great linear relationship (y = 53.04x - 3.474, R2 = 0.9936) with the concentrations (ranging from 0.1 to 10 mg/mL) when using CNC. Further investigation revealed that m/z 19,000 and m/z 21,000 peaks of Pueraria could be used for the adulteration analysis and post-translational modification research, demonstrating our method has the potential for broad applications.

Plasma-Excited Nebulizer Gas-Assisted Electrospray Ionization: Enhancing the Sensitivity of Pesticide in Mass Spectrometry.

Liquid chromatography-mass spectrometry (LC-MS) is widely used in the detection of pesticide residues. However, the detection sensitivity of low-polarity pesticides by commonly used electrospray ionization may be severely suppressed, which greatly affects the limit of detection and repeatability. Herein, a plasma-excited nebulizer gas-assisted electrospray ionization (PENG-ESI) device has been developed. By introducing the discharge plasma formed by Tesla coil into the electrospray nebulizer gas channel, the sensitivity of low-polarity pesticides was significantly increased while maintaining sensitivity to polar pesticides. Under the optimized conditions, the limit of detection for S-bioallethrin was achieved at the level of 100 pg/g with good linearity (R2 > 0.99) and precision (RSD ≤ 4.61%). The matrix effect of a series of spiked matrix samples is less than 13.1%. Finally, different pyrethroid pesticide residues were successfully analyzed without separation, highlighting that the technology has potential application prospects in food quality control, environmental monitoring, and other fields.

Switch in Selectivities by Dinuclear Nickel Catalysis: 1,4-Hydroarylation of 1,3-Dienes to Z-Olefins.

One of the most challenging tasks in organic synthesis is to control selectivities, especially switching the well-known selectivity to obtain new isomers that were previously inaccessible. Inspired by biological catalysis involving multiple metal centers, catalysis enabled by binuclear metal complexes offers the potential to induce reactivity and selectivity that might not be available to mononuclear catalysts. Herein, we describe that using a macrocyclic bis pyridyl diimine dinickel complex as the catalyst, the commonly observed 4,3-regioselectivity of hydroarylation of 1,3-dienes is switched to 1,4-hydroarylation with thermodynamically less stable Z-stereoselectivity, offering challenging synthetic target Z-olefins. DFT calculations show that the activation of 1,3-diene proceeds through dinuclear Ni-diolefin coordination, and the synergistic effects of two Ni nuclei enable reactivity and selectivity of this binuclear catalysis substantially different from those of mononuclear nickel complexes in the current reaction.

Coherence-OAM matrix properties of a twisted Gaussian Schell model beam.

Based on the cross-spectral density (CSD) function, the coherence-orbital angular momentum (COAM) matrix of twisted Gaussian Schell-model (TGSM) beam is proposed, and the COAM matrix is used to describe the correlation between OAM modes in TGSM optical field. The COAM matrix characteristics of TGSM beam are analyzed by numerical simulation. The results show that the COAM matrix characteristics of TGSM beam depend on the initial parameters of the beam. In addition, a method of generating TGSM beam by superposition of COAM matrix element modes is described, and the influence of different initial parameters on the superposition characteristics is studied. The results reveal the internal relationship between the coherent structure of the optical field, the twist phase and the OAM modes. Our work helps to explore new expressions of partially coherent beams and promote the practical application of optimizing partially coherent beams.

Research Progress on Machine Learning Assisted Non-Targeted Screening Strategy for Identification of Fentanyl Analogs.

In recent years, the types and quantities of fentanyl analogs have increased rapidly. It has become a hotspot in the illicit drug control field of how to quickly identify novel fentanyl analogs and to shorten the blank regulatory period. At present, the identification methods of fentanyl analogs that have been developed mostly rely on reference materials to target fentanyl analogs or their metabolites with known chemical structures, but these methods face challenges when analyzing new compounds with unknown structures. In recent years, emerging machine learning technology can quickly and automatically extract valuable features from massive data, which provides inspiration for the non-targeted screening of fentanyl analogs. For example, the wide application of instruments like Raman spectroscopy, nuclear magnetic resonance spectroscopy, high resolution mass spectrometry, and other instruments can maximize the mining of the characteristic data related to fentanyl analogs in samples. Combining this data with an appropriate machine learning model, researchers may create a variety of high-performance non-targeted fentanyl identification methods. This paper reviews the recent research on the application of machine learning assisted non-targeted screening strategy for the identification of fentanyl analogs, and looks forward to the future development trend in this field.

Insights into electrogenerated intermediates and rapid screening of electrochemical reactions by surface-modified carbon fiber paper redox spray ionization mass spectrometry.

The combination of electrochemistry and mass spectrometry is a powerful analytical tool for studying redox reaction mechanisms and identifying products or intermediates. However, the previously reported devices all require bespoke fabrication and are too complicated to be assembled and used by others. Crucially, the long ion transport distance and small spray volumes make it difficult to capture the short-lived intermediates. We present a practical mass spectrometric method in which surface-modified carbon fiber paper is innovatively applied to detect electrogenerated intermediates. Treating carbon fiber paper with dilute nitric acid removes its surface impurities, enhancing the capability of electro-redox. Electrospray ionization and redox reaction occur simultaneously on the tip of the paper. Transient electro-redox species generate and transfer into gas phase as soon as the appearance of spray. Rapid transport of quantities of electrogenerated ions to the mass spectrometer inlet makes it possible for mass spectrometric identification on the millisecond scale. The short-lived radical cations and iminium ions were successfully captured, reflecting the starting step of the cross-dehydrogenation coupling reaction. The real-time oxidation and online functionalization reactions of tertiary amines were achieved using this device without additional oxidants and electrolytes. In this way we could achieve in-depth mechanistic understanding and rapid screening of serial reactions.

Structural Analysis and Characterization of 4-F-α-PVP Analog 4-F-3-Methyl-α- PVP Hydrochloride.

OBJECTIVES: To identify 1-(4-fluorophenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-α-PVP) analog 1-(4-fluoro-3-methyl phenyl)-2-(1-pyrrolidinyl) pentan-1-one (4-F-3-Methyl-α-PVP) hydrochloride without reference substance. METHODS: The direct-injection electron ionization-mass spectrometry (EI-MS), GC-MS, electrospray ionization-high resolution mass spectrometry (ESI-HRMS), ultra-high performance liquid chromatography-high resolution tandem mass spectrometry (UPLC-HRMS/MS), nuclear magnetic resonance (NMR), ion chromatography and Fourier transform infrared spectroscopy (FTIR) were integrated utilized to achieve the structural analysis and characterization of the unknown compound in the sample, and the cleavage mechanism of the fragment ions was deduced by EI-MS and UPLC-HRMS/MS. RESULTS: By analyzing the direct-injection EI-MS, GC-MS, ESI-HRMS and UPLC-HRMS/MS of the compound in the samples, it was concluded that the unknown compound was a structural analog of 4-F-α-PVP, possibly with one more methyl group in the benzene ring. According to the analysis results of 1H-NMR and 13C-NMR, it was further proved that the methyl group is located at the 3-position of the benzene ring. Since the actual number of hydrogen in 1H-NMR analysis was one more than 4-F-3-Methyl-α-PVP neutral molecule, it was inferred that the compound existed in the form of salt. Ion chromatography analysis results showed that the compound contained chlorine anion (content 11.14%-11.16%), with the structural analysis of main functional group information by FTIR, the unknown compound was finally determined to be 4-F-3-Methyl-α-PVP hydrochloride. CONCLUSIONS: A comprehensive method using EI-MS, GC-MS, ESI-HRMS, UPLC-HRMS/MS, NMR, ion chromatography and FTIR to identify 4-F-3-Methyl-α-PVP hydrochloride in samples is established, which will be helpful for the forensic science laboratory to identify this compound or other analog compounds.

Cu-Mediated Thianthrenation and Phenoxathiination of Arylborons.

Great success in synthetic chemistry is motivated by the development of novel and reactive linchpins for carbon-carbon and carbon-heteroatom bond formation reactions, which has dramatically altered chemists' approach to building molecules. Herein, we report the ready synthesis of aryl sulfonium salts, a versatile electrophilic linchpin, via a novel Cu-mediated thianthrenation and phenoxathiination of commercially available arylborons with thianthrene and phenoxathiine, providing a series of aryl sulfonium salts in high efficiency. More importantly, by leveraging the sequential Ir-catalyzed C-H borylation and Cu-mediated thianthrenation of arylborons, the formal thianthrenation of arenes is also achieved. The Ir-catalyzed C-H borylation with undirected arenes normally occurred at the less steric hindrance position, thus providing a complementary method for thianthrenation of arenes in comparison with electrophilic thianthrenation. This process is capable of late-stage functionalization of a series of pharmaceuticals, which might find wide synthetic applications in both industry and academic sectors.

Ultrasonic sample introduction combined with flame assisted thermal ionization: Pretreatment-free direct mass spectrometry analysis for fraction collecting tubes of preparative liquid chromatography.

Ultrasonic sample introduction combined with flame assisted thermal ionization mass spectrometry (USI-FATI-MS) was developed to monitor the fractions of preparative liquid chromatography. Recently, ultrasound-based sample introduction techniques have achieved great advance in the field of high-throughput analysis. However, it is still a challenge to directly apply these existing techniques to the analysis of macro volume samples (mL level). In this work, ultrasonic sample introduction combined with flame assisted thermal ionization was used for pretreatment-free direct mass spectrometry analysis of micro to macro volume samples (µL-mL level). Utilizing this unique design of ultrasonic sample introduction, liquid sample in the container can be quickly atomized to the gas phase without contact. Then, due to the flame assisted thermal ionization source, desolvation and ionization of the sample droplets will occur immediately. USI-FATI-MS has shown excellent sensitivity, repeatability and great compatibility to solvents and compounds with a wide range of polarity. As a proof of concept, USI-FATI-MS has been applied for rapid monitoring and identification of purified synthetic and natural products in fractions.

Cobalt-Catalyzed Regiodivergent and Enantioselective Intermolecular Coupling of 1,1-Disubstituted Allenes and Aldehydes.

Catalytic enantioselective coupling of 1,1-disubstituted allenes and aldehydes through regiodivergent oxidative cyclization followed by stereoselective protonation or reductive elimination promoted by chiral phosphine-Co complexes is presented. Such processes represent unprecedented and unique reaction pathways for Co catalysis that enable catalytic enantioselective generation of metallacycles with divergent regioselectivity accurately controlled by chiral ligands, affording a wide range of allylic alcohols and homoallylic alcohols that are otherwise difficult to access without the need of pre-formation of stoichiometric amounts of alkenyl- and allyl-metal reagents in up to 92 % yield, >98 : 2 regioselectivity, >98 : 2 dr and >99.5 : 0.5 er.

Reactivity of vinylidene-π-allyl palladium(II) species.

The reactivity of a new type of organometallic intermediate, vinylidene-π-allyl palladium species, has been demonstrated: the reaction between 4-alken-2-ynyl carbonates and stabilized carbon nucleophiles afforded functionalized 1,2,3,-butatriene compounds in moderate to high yields and excellent regioselectivities.

Non-directed C-H arylation of electron-deficient arenes by synergistic silver and Pd3 cluster catalysis.

Transition-metal clusters have attracted great attention in catalysis due to their unique reactivity and electronic properties, especially for novel substrate binding and activation modes at the bridging coordination sites of metal clusters. Although palladium complexes have demonstrated outstanding catalytic performance in various transformations, the catalytic behaviors of polynuclear palladium clusters in many important synthetic methodologies remain much less explored so far. Herein, we disclose the use of an atomically defined tri-nuclear palladium (Pd3Cl) species as a catalyst precursor in Ag(I)-assisted direct C-H arylation with aryl iodides under mild conditions. This catalyst system leads to the formation of synthetically important biaryls in good yields with high site selectivities without the assistance of directing groups.

An online derivatization strategy targeting carbon-carbon double bonds by laser-ablation carbon fiber ionization mass spectrometry imaging: Unraveling the spatial characteristic in mountain-cultivated ginseng and garden-cultivated ginseng with different ages.

Serving as a world-renowned tonic, ginseng contains various types of bioactive metabolites. The comprehensive profiling of these metabolites may help explore the nutritional value of ginseng. Due to high variety in chemical structures, simultaneous monitoring of these metabolites remains a challenge. Herein, a high-throughput and high-selectivity online derivatization mass spectrometry imaging strategy targeting CC was developed. As a widely existed chemical group, CC acts like a bridge connecting different kinds of metabolites. [d0]/[d10]-Bis(pyridine) iodine tetrafluoroboride reagent was chosen for the derivatization of CC, the detection sensitivity of which increased about 3 magnitudes after derivatization. Assisted by laser ablation carbon fiber ionization mass spectrometry, the spatial distribution of bioactive metabolites in mountain-cultivated and garden-cultivated ginseng were visualized. The correlation heatmap results revealed that metabolites in mountain-cultivated ginseng hold higher correlation than those in garden-cultivated ginseng. The proposed method showed potential in providing comprehensive information on the nutrient content of foods.

Efficient determination of enantiomeric ratios of α-hydroxy/amino acids from fermented milks via ion mobility-mass spectrometry.

Chiral analysis of food components can provide important information for food quality, bioactivity and safety. Determination of enantiomeric ratios in food is a tedious task, due to the poor resolution and insufficient sensitivity for simultaneous discrimination and quantification of trace amounts of d-form metabolites. Herein, a high-throughput, high-sensitive and high-resolution method was developed for simultaneously determining enantiomeric ratios of multiple chiral α-hydroxy/amino acids (HA/AAs) from fermented milks in one-run by [d0]/[d5]-estradiol-3-benzoate-17ß-chloroformate labeling-assisted ion mobility - mass spectrometry. Results revealed extensive variation in chiral HA/AA profiles among 15 fermented milks. A total of 14 D-HA/AAs were identified. d-Lactic acid and d-alanine appeared as the most discriminatory in fermented milks with live lactic acid bacteria (LAB). Results suggested that glycolysis, casein hydrolysis and enantioisomerization of HA/AAs were most likely affected by various starter culture LAB. It may contribute to entail a valuable step forward in food quality control and discovering functional-related chiral biomarkers.

Mass Spectrometry Rearrangement Ions and Metabolic Pathway-Based Discovery of Indole Derivatives during the Aging Process in Citrus reticulata 'Chachi'.

The rapid analysis and characterization of compounds using mass spectrometry (MS) may overlook trace compounds. Although targeted analysis methods can significantly improve detection sensitivity, it is hard to discover novel scaffold compounds in the trace. This study developed a strategy for discovering trace compounds in the aging process of traditional Chinese medicine based on MS fragmentation and known metabolic pathways. Specifically, we found that the characteristic component of C. reticulata 'Chachi', methyl N-methyl anthranilate (MMA), fragmented in electrospray ionization coupled with collision-induced dissociation (CID) to produce the rearrangement ion 3-hydroxyindole, which was proven to exist in trace amounts in C. reticulata 'Chachi' based on comparison with the reference substance using liquid chromatography-tandem mass spectrometry (LC-MS/MS). Combining the known metabolic pathways of 3-hydroxyindole and the possible methylation reactions that may occur during aging, a total of 10 possible indole derivatives were untargeted predicted. These compounds were confirmed to originate from MMA using purchased or synthesized reference substances, all of which were detected in C. reticulata 'Chachi' through LC-MS/MS, achieving trace compound analysis from untargeted to targeted. These results may contribute to explaining the aging mechanism of C. reticulata 'Chachi', and the strategy of using the CID-induced special rearrangement ion-binding metabolic pathway has potential application value for discovering trace compounds.