Toward Conductive Additive Free Organic Electrode for Lithium-Ion Battery Using Supramolecular Columnar Organization.

With the aim to meet the greatest challenge facing organic batteries, namely the low conductivity of the electrodes, the electrochemical properties of a series of substituted perylene diimides able to form semi-conductive columnar material are investigated. Depending on the substituent group, a strong influence of this group on the reversibility, redox potential but especially on the gravimetric capacity of the electrodes is observed. In the case of substitution by a simple propyl group, the corresponding diimide shows a complete electrochemical activity with only 10% by mass of conductive additive and even shows a half-capacity activity without any additive and without particular electrode engineering. Extensive research has highlighted the intrinsic reactivity of the columnar material but also its perpetual rearrangement during charge/discharge cycles. This study shows that the amount of conductive additive can be significantly reduced by adapting the design of the molecular material and favoring the assembly of redox units in the form of a conductive column.

Mass Spectrometry, Ion Mobility Separation and Molecular Modelling: A Powerful Combination for the Structural Characterisation of Substituted Cyclodextrins Mixtures.

When working on the synthesis of substituted cyclodextrins (CDs), the main challenge remains the analysis of the reaction media content. Our objective in this study was to fully characterise a complex isomers mixture of Lipidyl-ßCDs (LipßCD) obtained with a degree of substitution 1 (DS = 1) from a one-step synthesis pathway. The benefit of tandem mass spectrometry (MS/MS) and ion mobility separation hyphenated with mass spectrometry (IM-MS) was investigated. The MS/MS fragment ion's relative intensities were analysed by principal component analysis (PCA) to discriminate isomers. The arrival time distribution (ATD) of each isomer was recorded using a travelling wave ion mobility (TWIM) cell allowing the determination of their respective experimental collision cross section (CCSexp). The comparison with the predicted theoretical CCS (CCSth) obtained from theoretical calculations propose a regioisomer assignment according to the ßCD hydroxyl position (2, 3, or 6) involved in the reaction. These results were validated by extensive NMR structural analyses of pure isomers combined with molecular dynamics simulations. This innovative approach seems to be a promising tool to elucidate complex isomer mixtures such as substituted cyclodextrin derivatives.

Combined LC-MS/MS and Molecular Networking Approach Reveals Antioxidant and Antimicrobial Compounds from Erismadelphus exsul Bark.

Erismadelphus exsul Mildbr bark is widely used in Gabonese folk medicine. However, little is known about the active compounds associated with its biological activities. In the present study, phytochemical profiling of the ethanolic extract of Erismadelphus exsul was performed using a de-replication strategy by coupling HPLC-ESI-Q/TOF with a molecular network approach. Eight families of natural compounds were putatively identified, including cyclopeptide alkaloids, esterified amino acids, isoflavonoid- and flavonoid-type polyphenols, glycerophospholipids, steroids and their derivatives, and quinoline alkaloids. All these compounds were identified for the first time in this plant. The use of molecular networking obtained a detailed phytochemical overview of this species. Furthermore, antioxidant (2,2-diphenyl-1-picryl-hydrazylhydrate (DPPH) and ferric reducing capacity (FRAP)) and in vitro antimicrobial activities were assessed. The crude extract, as well as fractions obtained from Erismadelphus exsul, showed a better reactivity to FRAP than DPPH. The fractions were two to four times more antioxidant than ascorbic acid while reacting to FRAP, and there was two to nine times less antioxidant than this reference while reacting to DPPH. In addition, several fractions and the crude extract exhibited a significant anti-oomycete activity towards the Solanaceae phytopathogen Phytophthora infestans in vitro, and, at a lower extent, the antifungal activity against the wheat pathogen Zymoseptoria tritici had growth inhibition rates ranging from 0 to 100%, depending on the tested concentration. This study provides new insights into the phytochemical characterization and the bioactivities of ethanolic extract from Erismadelphus exsul bark.

IL versus DES: Impact on chitin pretreatment to afford high quality and highly functionalizable chitosan.

Chitin is mainly extracted from crustaceans, but this resource is seasonally dependent and can represent a major drawback to satisfy the traceability criterion for high valuable applications. Insect resources are valuable alternatives due to their lower mineral content. However, the deacetylation of chitin into chitosan is still an expensive process. Therefore, we herein compare the impact of both DES/IL-pretreatments on the efficiency of the chemical deacetylation of chitin carried out over two insect sources (Bombyx eri, BE and Hermetia illucens, HI) and shrimp shells (S). The results showed that chitosans obtained from IL-pretreated chitins from BE larva, present lower acetylation degrees (13-17%) than DES-pretreated samples (18-27%). A selective N-acylation reaction with oleic acid has also been performed on the purest and most deacetylated chitosans leading to high substitution degrees (up to 27%). The overall approach validates the proper chitin source and processing methodology to achieve high quality and highly functionalizable chitosan.

Processing of NMR and MS metabolomics data using chemometrics methods: a global tool for fungi biotransformation reactions monitoring.

INTRODUCTION: Biotransformation constitutes an important aspect of the drug discovery process, to mimic human metabolism of active principal ingredient but also to generate new chemical entities. Several microorganisms such as fungi are well adapted to transform drug, whether at the stage of screening or for large-scale production. OBJECTIVES: Due to the high chemical complexity of the biotransformation media, it seems attractive to develop new analytical strategies in order to guarantee an adequate monitoring and optimize the production of targeted metabolites or drug candidates. METHODS: The model designed for this purpose concerns the biotransformation of a potential histamine H3 antagonist (S38093) in order to produce phase I metabolites. MS, NMR and chemometrics tools were used to monitor biotransformation reactions. RESULTS: First, a screening of eleven filamentous fungi was carried out by UHPLC-UV-MS and principal component analysis to select the best candidates. Subsequently, MS (tR, m/z) and NMR (1H, JRES) fingerprints associated with Consensus OPLS-DA multiblock approach were used to better understand the bioreaction mechanisms in terms of nutrient consumption and hydroxylated metabolites production. Then an experimental design was set up to optimize the production conditions (pH, kinetic) of these target metabolites. CONCLUSION: This study demonstrates how NMR and MS acquisitions combined with chemometric methods offer an innovative analytical strategy to have a grasp of functionalization mechanisms, and identify metabolites and other compounds (amino acids, nutrients, etc.) in complex biotransformation mixtures.

A Deeper Investigation of Drug Degradation Mixtures Using a Combination of MS and NMR Data: Application to Indapamide.

A global approach that is based on a combination of mass spectrometry (MS) and nuclear magnetic resonance (NMR) data has been developed for a complete and rapid understanding of drug degradation mixtures. We proposed a workflow based on a sample preparation protocol that is compatible to MS and NMR, the selection of the most appropriate experiments for each technique, and the implementation of prediction software and multivariable analysis method for a better interpretation and correlation of MS and NMR spectra. We have demonstrated the efficient quantification of the remaining active pharmaceutical ingredient (API). The unambiguous characterization of degradation products (DPs) was reached while using the potential of ion mobility-mass spectrometry (IM-MS) for fragment ions filtering (HDMSE) and the implementation of two-dimensional (2D) NMR experiments with the non-uniform sampling (NUS) method. We have demonstrated the potential of quantitative NMR (qNMR) for the estimation of low level DPs. Finally, in order to simultaneously monitor multi-samples, the contribution of partial least squares (PLS) regression was evaluated. Our methodology was tested on three indapamide forced degradation conditions (acidic, basic, and oxidative) and it could be easily transposed in the drug development field to assist in the interpretation of complex mixtures (stability studies, impurities profiling, and biotransformation screening).

In Vivo Use of 1D and 2D 1H NMR to Examine the Glycosylation of Scopoletin in Duboisia myoporoides Cell Suspensions.

Cell suspensions initiated from Duboisia myoporoides-a shrub belonging to the Solanaceae family and being a rich source of tropane alkaloids-previously showed their ability to glycosylate scopoletin into scopolin, which represent coumarins showing health benefits. To investigate the time course of this glycosylation reaction, an in vivo NMR approach was developed using a perfusion system in an 8-mm NMR tube and 1H NMR with 1D and 2D (TOCSY and NOESY) experiments. The time course of metabolic changes could therefore be followed without any labeling.

Use of qNMR for speciation of flaxseeds (Linum usitatissimum) and quantification of cyanogenic glycosides.

This report describes a routine method taking less than 20 min to quantify cyanogenic glycosides such as linustatin and neolinustatin from flaxseeds (Linum usitatissimum L.) using 1H nuclear magnetic resonance. After manual dehulling, a higher linustatin content was shown in the almond fraction, while neolinustatin and total cyanogenic glycoside contents were significantly higher in hulls. Linustatin and neolinustatin were quantified in seven cultivars grown in two locations in three different years. Linustatin, neolinustatin, and total cyanogenic glycosides ranged between 91 and 267 mg/100 g, 78-272 mg/100 g, and 198-513 mg/100 g dry weight flaxseeds, respectively. NMR revealed differences of up to 70% between samples with standard deviation variations lower than 6%. This study shows that NMR is a very suitable tool to perform flaxseed varietal selection for the cyanogenic glycoside content. Graphical abstract qNMR can be used to perform flaxseed varietal selection for the cyanogenic glycoside content.

Arylnaphthalene and aryltetralin-type lignans in hairy root cultures of Linum perenne, and the stereochemistry of 6-methoxypodophyllotoxin and one diastereoisomer by HPLC-MS and NMR spectroscopy.

INTRODUCTION: Hairy root cultures of Linum sp. are an alternative for the high production of lignans. Linum perenne is known to produce arylnaphthalene-type lignans such as justicidin B, isojusticidin and diphyllin. OBJECTIVE: To elucidate the presence of aryltetralin-type lignan diastereoisomers, besides the known arylnaphthalene-type lignans, in hairy roots of Linum perenne, and to determine the configurations of one diastereoisomer of 6-methoxypodophyllotoxin (6-MPTOX). METHODS: Lignans from hairy root cultures of Linum perenne were extracted and separated by HPLC. Arylnaphthalene-type lignans were identified by LC-MS, according to the literature. Two diastereoisomers of aryltetralin-type lignans were analysed by mass spectrometry and NMR spectroscopy. RESULTS: Numerous arylnaphthalene-type lignans (diphyllin-2-hexose-pentose, diphyllin-3-pentose and diphyllin-hexose) were identified in hairy root cultures. Methoxypodophyllotoxin, an aryltetralin-type lignan, was also identified, as well as one diastereoisomer. This aryltetralin-type lignan could be derived via 7-hydroxymatairesinol as a hypothetical biosynthetic pathway. The stereochemical configurations of aryltetralin isomers were determined. CONCLUSION: Arylnaphthalene and two diastereoisomers of aryltetralin-type lignans are produced in Linum perenne hairy root cultures. Matairesinol, the precursor of justicidin B, also seems to be converted into 6-MPTOX via 7-hydroxymatairesinol. This is the first report of the stereochemical configurations of an aryltetralin-type lignan other than podophyllotoxin (PTOX).

5-O-caffeoylshikimic acid from Solanum somalense leaves: advantage of centrifugal partition chromatography over conventional column chromatography.

Solanum somalense leaves, used in Djibouti for their medicinal properties, were extracted by MeOH. Because of the high polyphenol and flavonoid contents of the extract, respectively, determined at 80.80 ± 2.13 mg gallic acid equivalent/g dry weight and 24.4 ± 1.01 mg quercetin equivalent/g dry weight, the isolation and purification of the main polyphenols were carried out by silica gel column chromatography and centrifugal partition chromatography. Column chromatography led to 11 enriched fractions requiring further purification, while centrifugal partition chromatography allowed the easy recovery of the main compound of the extract. In a solvent system composed of CHCl3/MeOH/H2O (9.5:10:5), 21.8 mg of this compound at 97% purity was obtained leading to a yield of 2.63%. Its structure was established as 5-O-caffeoylshikimic acid by mass spectrometry and NMR spectroscopy. This work shows that S. somalense leaves contain very high level of 5-O-caffeoylshikimic acid (0.74% dry weight), making it a potential source of production of this secondary metabolite that is not commonly found in nature but could be partly responsible of the medicinal properties of S. somalense leaves.

Benefits of methylated cyclodextrins in the development of midazolam pharmaceutical formulations.

Midazolam (MDZ) is a benzodiazepine commonly administered in preanesthesia of children by oral or by sublingual routes. To mask its bitter taste and enhance its aqueous solubility, we already developed a 0.2% (w/v) MDZ oral solution containing γ-cyclodextrin (γ-CD), which proves to be better accepted by children in pediatrics at University Hospital of Amiens. To improve the MDZ solubility, its closed form proportion in acidobasic equilibrium and its chemical stability, nuclear magnetic resonance, liquid chromatography-electrospray-high-resolution mass spectrometry, and tandem mass spectrometry methods were used to highlight the advantages of using partially methylated CD (2,6 di-O-methyl-ß-cyclodextrin) and randomized methylated-ß-cyclodextrin (RAMEB). The formation of 1:1 inclusion complex offered an improvement of the MDZ solubility and an increase of the closed and pharmacologically active form with a 33% gain when compared with the aqueous solution without CD. It was also demonstrated that RAMEB had a protecting effect on the MDZ degradation because it was found in almost 95% of remaining MDZ solution after 3 months at 40°C.

Influence of common preanalytical variations on the metabolic profile of serum samples in biobanks.

A blood pre-centrifugation delay of 24 h at room temperature influenced the proton NMR spectroscopic profiles of human serum. A blood pre-centrifugation delay of 24 h at 4°C did not influence the spectroscopic profile as compared with 4 h delays at either room temperature or 4°C. Five or ten serum freeze-thaw cycles also influenced the proton NMR spectroscopic profiles. Certain common in vitro preanalytical variations occurring in biobanks may impact the metabolic profile of human serum.

Enzymatic hydrolysis of ionic liquid-pretreated celluloses: contribution of CP-MAS 13C NMR and SEM.

The supramolecular structure of four model celluloses was altered prior to their enzymatic saccharification using two ionic liquid pretreatments: one with the commonly used 1-ethyl-3-methylimidazolium acetate ([Emim](+)[CH(3)COO](-)) and the other with the newly developed 1-ethyl-3-methylimidazolium methylphosphonate ([Emim](+)[MeO(H)PO(2)](-)). The estimation of crystallinity index (CrI) by solid state (13)C nuclear magnetic resonance for each untreated/pretreated celluloses was compared with the performances of their enzymatic hydrolysis. For α-cellulose, both pretreatments led to a significant decrease in CrI from 25% to 5% but had no effect on glucose yields. In contrast, The [Emim](+)[MeO(H)PO(2)](-) pretreatment on the long fibers of cellulose had no significant effect on the CrI although a conversion yield in glucose of 88% is obtained versus 32% without pretreatment. However, scanning electron microscopy analysis suggested a loss of fiber organization induced by both ionic liquid pretreatments leading to a larger accessibility by cellulases to the cellulose surface.

Osmoregulated trehalose-derived oligosaccharides in Sinorhizobium meliloti.

Sinorhizobium meliloti is a soil bacterium accumulating glutamate, N-acetylglutaminyl glutamine amide and trehalose in hyperosmolarity. Besides these compatible solutes, we highlighted several compounds in S. meliloti Rm1021 wild-type strain. The purification and the structural characterization based on liquid chromatography evaporative light scattering detector, electrospray ionization high resolution mass spectrometry and nuclear magnetic resonance techniques showed they were four linear oligosaccharides composed of 3, 4, 5 and 6 glucose units all linked by alpha-(1-->2) linkages except a terminal alpha-(1<-->1) linkage. These oligosaccharides were cytoplasmic and were observed in several wild-type strains suggesting they were common features in S. meliloti strains grown in hyperosmolarity.

Metabolic profiling of maize mutants deficient for two glutamine synthetase isoenzymes using 1H-NMR-based metabolomics.

INTRODUCTION: Maize mutants deficient for the expression of two genes encoding cytosolic glutamine synthetase (GS) isoenzymes GS1.3 and GS1.4 displayed reduced kernel number and kernel size, respectively, the effect of the mutation being cumulative in the double mutant. However, at maturity, shoot biomass production was not modified in all the mutants, indicating that the reaction catalysed by the enzyme is specifically involved in the control of grain yield. OBJECTIVE: To examine the physiological impact of the GS mutations on the leaf metabolic profile during the kernel filling period, during which nitrogen is remobilized from the shoots to be further exported to the kernels. METHODOLOGY: An (1)H-NMR spectroscopy metabolomic was applied to the investigation of metabolic change of the gln1.3, gln1.4 and gln1.3/1.4 double mutant. RESULTS: In the three GS mutants, an increase in the amount of several N-containing metabolites such as asparagine, alanine, threonine and phophatidylcholine was observed whatever the level of nitrogen fertilisation. In addition, we found an accumulation of phenylalanine and tyrosine, two metabolites involved the primary steps of the phenylpropanoid pathway. CONCLUSION: Changes in the metabolic profile of the GS mutants suggest that, when cytosolic GS activity is strongly reduced, either alternative metabolic pathways participate in the reassimilation of ammonium released during leaf protein remobilization or that premature leaf senescence is induced when kernel set and kernel filling are affected. The accumulation of phenylalanine and tyrosine in the mutant plants indicates that lignin biosynthesis is altered, thus possibly affecting ear development.

Coniferin dimerisation in lignan biosynthesis in flax cells.

[(13)C(2)]-Coniferin was provided to a flax (Linum usitatissimum L.) cell suspension to monitor subsequent dimerisation by MS and NMR. The label was mainly incorporated into a 8-8'-linked lignan, lariciresinol diglucoside, a 8-5'-linked neolignan, dehydrodiconiferyl alcohol glucoside and a diastereoisomeric mixture of a 8-O-4'-linked neolignan, guaiacylglycerol-beta-coniferyl alcohol ether glucoside. This latter compound is reported for the first time in flax. The strong and transient increase in these compounds in fed cells was concomitant with the observed peak in coniferin content. These results suggest (i) a rapid metabolisation of coniferin into lignans and neolignans and indicate the capacity of flax cells to operate different types of couplings, and (ii) a continuous synthesis and subsequent metabolisation of coniferin-derived dimers all over the culture period.