David Mathiron

Boron esters as tunable anion carriers for non-aqueous batteries electrochemistry.

Compounds like LiF, Li(2)O, and Li(2)O(2) have considerable importance in batteries; the first two are ubiquitous in the protective SEI at the negative electrode, or the result of conversion reactions with fluorides and oxides. The latter, Li(2)O(2,) forms from oxygen reduction in the much vaunted Li/air batteries. Mastering their solubility in Li-based electrolytes is viewed as essential for further progress in battery safety, lifetime, or capacity. Aprotic solvents cannot provide the H-bonds necessary to their dissolution, and simple practical solutions have yet to materialize. Here we disclose a novel and large family of boron esters of general formula Y-C((CH(2)O)(Z(1)O)(Z(2)O))B whose Lewis acidity stems from geometrical constraint and can be tuned via electron affinity either by Y = CH(3) --> Y = NO(2) or Z(1,2) = CH(2) --> Z(1,2) = CO so as to partially or fully dissolve the above compounds both in battery solvent EC/DMC and in DMF. The extreme simplicity of synthesis and variability of these boron-based anion carriers, where the exchange rate is fast, are not only a valuable addition to coordination science but also a step forward to improve present battery systems.

Development and formulation of a 0.2% oral solution of midazolam containing γ-cyclodextrin

In absence of dedicated children formulation, intravenous formulations of midazolam, which exhibit strong bitterness, are occasionally used for oral or sublingual administration. In order to improve the quality and the acceptance by children of a midazolam anesthesia premedication, a new 0.2% (w/v) aqueous solution for oral administration has been prepared. The final formulation was obtained by the adjunction of a sweetener (sucralose), an aroma (orange aroma) and gamma-cyclodextrin to a citric acid solution of midazolam. The gamma-cyclodextrin forms an inclusion complex with the hydrophobic midazolam as evidenced using nuclear magnetic resonance spectroscopy (stoichiometry 1:1, K=283 M(-1)). A sterile filtration method was selected for the formulation microbial preservation using liquid chromatography coupled to high resolution mass spectrometry (LC-HRMS). Finally, a routine high performance liquid chromatography (HPLC) method is proposed for the quantitative determination of global midazolam amount in the pharmaceutical preparation.

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-β-cyclodextrin) and randomized methylated-β-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.

Tropane alkaloid profiling of hydroponic Datura innoxia Mill. Plants inoculated with Agrobacterium rhizogenes.

INTRODUCTION Hydroponics has been shown as a possible way to produce high quality plant biomass with improved phytochemical levels. Nevertheless, effects of plant biotic and abiotic environment can lead to drastic changes and plant growth conditions must be optimised. OBJECTIVE To evaluate how much microbes and Agrobacterium rhizogenes TR7 wild strain may affect the tropane alkaloid profile in Datura innoxia Mill. plants cultivated in hydroponic conditions. METHODOLOGY Datura innoxia Mill. plants were cultivated in hydroponic with sterile or non-sterile conditions. For half of the non-sterile plants, Agrobacterium rhizogenes TR7 strain was added to the nutrient solution for hydroponics. The tropane alkaloid content of leaves and roots was analysed by UFLC/ESI-HRMS and MS/MS. The metabolite profiles were compared using partial least square-discriminant analysis. RESULTS In sterile conditions, aerial parts contained more scopolamine than the roots. However, the diversity of tropane alkaloids was greater in roots. Furthermore, 21 known compounds and four non-elucidated tropane alkaloids were found. The tropane alkaloid profile was shown to be statistically different between sterile and non-sterile hydroponic conditions. The levels of 3-acetoxy-6-hydroxytropane and 3-hydroxylittorine were higher in plants inoculated with A. rhizogenes. Five other tropane compounds were found in higher amounts in non-axenic control plants. Hyoscyamine and scopolamine total contents were much higher in the whole plant co-cultivated with A. rhizogenes TR7 than in controls. Furthermore, the leaves and roots of axenic plants contained more alkaloids than non-sterile ones. CONCLUSION In hydroponic conditions, microbes induced variations of the phytochemical levels. Addition of A. rhizogenes TR7 into the nutrient solutions improved the total hyoscyamine and scopolamine production.

A Combined Approach of NMR and Mass Spectrometry Techniques Applied to the α-Cyclodextrin/Moringin Complex for a Novel Bioactive Formulation †

Moringin, obtained via enzymatic conversion of the glucosinolate precursor glucomoringin, is an uncommon member of the isothiocyanate class, and has been proven to possess a broad range of biological activities such as antitumor activity, protection against neurodegenerative disorders and bactericidal effects. Since moringin is weakly soluble in water and unstable in aqueous medium, cyclodextrins (CDs) were considered for the development of a new moringin formulation, with a view to improving its solubility and stability in aqueous solution for use as an anti-inflammatory. A combined structural study using proton nuclear magnetic resonance (1H-NMR), diffusion-ordered spectroscopy (DOSY) and ion mobility mass spectrometry (IM-MS) is reported, highlighting the formation of a 1:1 α-CD/moringin inclusion complex. The association constant K was determined (1300 M−1 at 300 K). Completion of the structural characterization was performed by T-ROESY and MS/MS experiments, which evidenced the mode of penetration of moringin into α-CD. Finally, the “chaperone-like” properties of α-CD with respect to the stability of moringin have been highlighted.

Flax phenolic compounds as inhibitors of lipid oxidation: Elucidation of their mechanisms of action

Polyunsaturated fatty acids are particularly sensitive to the damages due to reactive oxygen species and lipid oxidation has been reported to be involved in the degradation of food as well as in the early stages of several diseases. Our objective was to study the mechanisms of action of flax (Linum usitatissimum) phenolic compounds to prevent membrane lipid oxidation. To do so, several biophysical techniques (oxidative stress, surface tension, fluorescence spectroscopy and HPLC) were used to investigate the ability of the compounds to prevent lipid oxidation and to interact with membranes. We evidenced a relationship between the structure and the antioxidant efficiency as aglycone compounds were significantly more efficient (p < 0.05) than glucoside compounds. In addition, our results revealed that aglycone lignans spontaneously penetrated the membrane contrary to aglycone hydroxycinnamic acids. To conclude, the comparison of the antioxidant efficiencies revealed that membrane inserted compounds better inhibited lipid oxidation than non-inserted compounds.

Selective Synthesis of 3-O-Palmitoyl-Silybin, a New-to-Nature Flavonolignan with Increased Protective Action against Oxidative Damages in Lipophilic Media

A selective acylation protocol using cerium chloride (CeCl3) as catalyst was applied to functionalize silybinin (1), a natural antioxidant flavonolignan from milk thistle fruit, in order to increase its solubility in lipophilic media while retaining its strong antioxidant activity. The selective esterification of 1 at the position 3-OH with a palmitate acyl chain leading to the formation of the 3-O-palmitoyl-silybin (2) was confirmed by both mass spectroscopy (MS) and nuclear magnetic resonance (NMR) analyses. The antioxidant activity of 1 was at least retained and even increased with the CUPRAC assay designed to estimate the antioxidant activity of both hydrophilic and lipophilic compounds. Finally, the 3-O-palmitoylation of 1, resulting in the formation of 2, also increased its anti-lipoperoxidant activity (i.e., inhibition of conjugated diene production) in two different lipophilic media (bulk oil and o/w emulsion) subjected to accelerated storage test.

A BAHD neofunctionalization promotes tetrahydroxycinnamoyl spermine accumulation in the pollen coats of the Asteraceae family

In eudicotyledons, accumulation of trihydroxycinnamoyl spermidine that is restricted to the pollen wall constitutes an evolutionary conserved trait. However, the role of this compound, which is synthetized by the BAHD enzyme spermidine hydroxycinnamoyl transferase (SHT), is still a matter of debate. Here, we show that this particular phenolamide is replaced by tetrahydroxycinnamoyl spermine in the pollen coat of the Asteraceae. Phylogenetic analyses combined with quantitative RT-PCR experiments allowed the identification of two homologous genes from Cichorium intybus (chicory) putatively involved in its metabolism. In vitro biochemical characterization of the two enzymes, named CiSHT1 and CiSHT2, confirmed the capability of recombinant proteins to synthesize spermine as well as spermidine derivatives. The wild-type metabolic phenotype was partially restored in an Arabidopsis sht mutant expressing CiSHT2. Strikingly, the transgenic plants also accumulated spermine derivatives that were absent in the wild-type. Overexpression of CiSHT2 in chicory hairy roots led to the accumulation of spermine derivatives, confirming its in vivo function. Complementary sequence analyses revealed the presence of an amino acid motif typical of the SHTs among the BAHD enzyme family. Our results highlight a recent neofunctionalization among the SHTs that has promoted the emergence of new phenolamides in the Asteraceae, which could potentially have contributed to the evolutionary success of this family.

Isolation and partial characterization of four fluorophores formed by nonenzymatic browning of methylglyoxal and glutamine-derived ammonia.

An aqueous solution of L‐glutamine (50 mmol/L) and methylglyoxal (100 mmol/L) was incubated at 120°C for 3 h in a 200 mmol/L phosphate buffer (pH 7.4). Four major fluorophores were revealed on the HPLC chromatogram. The same four fluorophores were obtained from the heating of a mixture of ammonia and methylglyoxal. After purification and concentration, they were structurally characterized by electrospray ionization mass spectrometry (ESI‐MS) using the high resolution and tandem mass spectrometry capabilities of a quadrupole time‐of‐flight MS. The accurate mass measurement of their [M+H]+ ions, the MS fragment patterns, and the presence of one to two nitrogen indicate the formation of fluorophores with molecular formulas of C7H7NO3, C8H9NO3, C12H14N2O4, and C12H14N2O5. These results show that, in an aqueous solution, free glutamine undergoes a rapid degradation, leading to the formation of ammonia which reacts with methylglyoxal to form fluorescent heterocyclic Maillard products.