Synthesis of trehalose-based chemical tools for the study of the mycobacterial membrane

Corynebacteriales including the causative agent of many diseases such as tuberculosis are known to be extremely resistant against external stress as well as to antibiotic treatments which is believed to be related to the singular architecture of their mycomembrane. Over the last decades, both bioorthogonal chemical reporters and fluorescent probes for the metabolic labeling of bacterial cell glycans were developed including several trehalose-based probes to study the dynamics of mycomembrane components. This review presents an exhaustive view on the reported syntheses of trehalose-based probes enabling the study of the mycomembrane biogenesis

Synthèse stéréosélective de 2-aminobutan-1, 3, 4-triols anti (approches synthétiques de la(-)bulgécinine et de la sous-unité ribosyl-diazépanone des liposidomycines)

Une voie de synthèse de 2-aminobutan-1,3,4-triols anti protégés de façon orthogonale a été développée. La stéréochimie a été contrôlée par deux étapes clés : une hydrogénation asymétrique de -cétoesters en présence de catalyseurs chiraux du ruthénium suivie d'une amination électrophile diastéréosélective des -hydroxyesters résultants. Ces composés ont été utilisés comme intermédiaires de synthèse, en particulier pour l'obtention de pyrrolidines fonctionnalisées précurseurs de la (+)- et de la (-)-bulgécinine. D'autre part, des analogues structuraux de la sous-unité ribosyl-diazépanone des liposidomycines ont été synthétisés par une voie convergente et diastéréosélective. La formation de la diazépanone a été effectuée par couplage entre un acide -aminé -hydroxylé dérivé du D-ribose et un aminoaldéhyde par une réaction d'amination réductrice suivie d'une macrolactamisationA synthetic route to orthogonally protected anti 2-aminobutan-1,3,4-triols was developed. Stereochemistry was controlled in two key steps : asymmetric hydrogenation of -ketoesters in the presence of chiral ruthenium catalysts was followed by diastereoselective electrophilic amination of the resulting -hydroxyesters. These compounds were used as synthetic intermediates, in particular to obtain functionalised pyrrolidine precursors of (+)- and (-)-bulgecinine. Structural analogues of the ribosyl-diazepanone sub-unit of the liposidomycines were synthesized by convergent diastereoselective route. The diazepanone was formed by coupling an -amino- -hydroxy acid derived from D-ribose with an aminoaldehyde by reductive amination followed by macrolactamisationVERSAILLES-BU Sciences et IUT (786462101) / SudocSudocFranceF

Synthesis of a <i>Mycobacterium tuberculosis</i> Tetra-acylated Sulfolipid Analogue and Characterization of the Chiral Acyl Chains Using Anisotropic NAD 2D-NMR Spectroscopy

Tetra-<i>O</i>-acylated sulfolipids are metabolites found in the cell wall of <i>Mycobacterium tuberculosis</i>, the causative agent of tuberculosis. Their role in pathogenesis remains, however, undefined. Here we describe a novel access to model tetra-<i>O</i>-acylated trehalose sulfate derivatives having simple acyl chains. The trehalose core was regioselectively protected using a tandem procedure with catalytic iron­(III) chloride hexahydrate and further desymmetrized. Model chiral fatty acids, prepared by a zinc-mediated cross-coupling, were incorporated into the trehalose core. The enantiomeric excess of the chiral fatty acids has been measured by natural abundance deuterium (NAD) 2D-NMR spectroscopy in a polypeptide based chiral liquid crystal. The synthetic approach established for the model compounds can easily be developed for the preparation of other analogues and natural sulfolipids

Hydrogen peroxide-responsive triggers based on borinic acids: molecular insights into the control of oxidative rearrangement

International audienceArylborinic acids represent new, efficient, and underexplored hydrogen peroxide-responsive triggers. In contrast to boronic acids, two concomitant oxidative rearrangements are involved in the complete oxidation of these species, which might represent a major limitation for an efficient effector (drug or fluorophore) release. Herein, we describe a comprehensive study of H2O2-mediated unsymmetrical arylborinic acid oxidation to investigate the factors that could selectively guide their oxidative rearrangement. The o-CF3 substituent was found to be an excellent directing group since complete regioselectivity was obtained on borinic acid models. This result was successfully applied to synthesizing new borinic acid-based fluorogenic probes, which exclusively release the fluorescent moiety upon H2O2 treatment. These compounds maintained their superior kinetic properties compared to boronic acids, thus further enhancing the potential of arylborinic acids as valuable new H2O2-sensitive triggers

Characterization of Protonated Model Disaccharides from Tandem Mass Spectrometry and Chemical Dynamics Simulations

International audienceThe fragmentation mechanisms of prototypical disaccharides have been studied herein by coupling tandem mass spectrometry (MS) with collisional chemical dynamics simulations. These calculations were performed by explicitly considering the collisions between the protonated sugar and the neutral target gas, which led to an ensemble of trajectories for each system, from which it was possible to obtain reaction products and mechanisms without pre‐imposing them. The β‐aminoethyl and aminopropyl derivatives of cellobiose, maltose, and gentiobiose were studied to observe differences in both the stereochemistry and the location of the glycosidic linkage. Chemical dynamics simulations of MS/MS and MS/MS/MS were used to suggest some primary and secondary fragmentation mechanisms for some experimentally observed product ions. These simulations provided some new insights into the fundamentals of the unimolecular dissociation of protonated sugars under collisional induced dissociation conditions

First access to a mycolic acid-based bioorthogonal reporter for the study of the mycomembrane and mycoloyltransferases in Corynebacteria

In this study, we report the first synthesis of an alkyne-based trehalose monomycolate probe containing a β-hydroxylated fatty acid and an α-branched chain similar to those of the natural mycolic acid. We demonstrate its utility for the labeling of the mycomembrane of Corynebacteria as well as for the study of mycoloyltransferases

Borinic Acids as New Fast-Responsive Triggers for Hydrogen Peroxide Detection.

Detection of hydrogen peroxide (H2O2), which is responsible for numerous damages when overproduced, is crucial for a better understanding of H2O2-mediated signalling in physiological and pathological processes. For this purpose, various“off-on” small fluorescent probes relying on a boronate trigger have been developed. However, they suffer from low kinetics and do not allow forH2O2-detectionwith a short response time. Therefore, more reactive sensors are still awaited. To address this issue, we have successfully developed the first generation of borinic-based fluorescent probes containing a coumarin-scaffold. We determined the in vitrokinetic constants of the probe toward H2O2-promotedoxidation. We measured 1.9x104m-1.s-1as a second order rate constant, which is 10 000 faster than its boronic counterpart (1.8 m-1.s-1). This remarkable reactivity was also effective in a cellular context, rendering the borinic trigger an advantageous new tool for H2O2detection

Synthesis of chemical tools to label the mycomembrane of corynebacteria using modified iron( iii ) chloride-mediated protection of trehalose

International audienceRegioselective protection of trehalose allows the fast synthesis of chemical tools for the study of the mycomembrane