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Glycolipids incorporating positive charges, mediated by an imidazolium cation, have shown potential for effective formulation of vesicular drug carriers, reflecting repulsive electrostatic forces, promoting the formation of nanosized assemblies and preventing unwanted Oswald ripening (Goh et al. (2019), ACS Omega 4 , 17,039). Our continuous development of an assembly-based drug delivery system prompted us to investigate a pH-sensitive analogue, leading to the synthesis of a 6-amino-Guerbet glycoside. However, in contrast to the imidazolium counterpart, the amine-mediated charge increased the intermolecular cohesions, furnishing bigger assemblies instead, which further increased upon introduction of acid. Moreover, assemblies exhibited a significantly reduced positive charge density. It is concluded that strong proton-initiated hydrogen bonding between amino groups provide cohesive head group interactions overcompensating possible repulsive charge interactions. While this behavior invalidates the application of the amino-glucoside as dispersing agent for the formulation of small vesicles, it potentially paves a route towards enhanced vesicle stability. [Display omitted] • Assemblies of amino-derivatized glycolipids are stabilized by hydrogen bonding. • The assembly stability of amino-derivatized glycolipids increases in acid. • Acid-induced amino group cohesion overcompensates possible charge repulsion. • Imidazolium-stabilized glycolipid vesicles experience Oswald ripening at 30 °C. [ABSTRACT FROM AUTHOR]

The hexasaccharide arabinan domain of Mycobacterial Arabinogalactan was provided with the versatile methodology toward β-selective arabinofuranosylation directed by B(C 6 F 5) 3 , demonstrating the effectiveness of the β-arabinofuranosylation strategy. Derivatization of the amino moiety at the reducing end are essential prerequisites for elucidating the biosynthetic pathway and conjugating of this compound to a protein carrier for vaccine generation. [Display omitted] • β-Arabinofuranosylation was achieved by the activation with B(C 6 F 5) 3. • The effectiveness of the β-arabinofuranosylation strategy has been demonstrated. • The compound can conjugate to protein carrier for further vaccine generation. [ABSTRACT FROM AUTHOR]

Neuraminic acid (Neu5Ac, also known as sialic acid) is an important monosaccharide found in glycoproteins and glycolipids which plays a vital role in regulation of physiological functions and pathological conditions. The study of sialoglycans has benefitted from the development of glycomimetic probes and inhibitors for proteins and enzymes that interact with and modify neuraminic acid in glycan chains. Methods to access sialoside intermediates with high yield are needed to facilitate the design of new targets. Here, we report the synthesis of C5-azido thiosialosides using a mild method to deprotect the C5-acetamido functional group followed by the use of a diazo-transfer reagent. We examined two diazo-transfer strategies and compared their yields and tolerance of acetate protecting groups. The same methods and comparisons were also performed for the 2,3-dehydro-5- N -acetylneuraminic acid (DANA) scaffold which is commonly used to generate inhibitors of neuraminidase (sialidase) enzymes. We found that C5-azido derivatives of both thiosialosides and DANA could be produced in five or six steps with yields up to 76 % and 83 %, respectively. Diazo-transfer reagents compared in this study were trifluoromethanesulfonyl azide (TfN 3) and imidazole-1-sulfonyl azide (ImzSO 2 N 3). We found that both reagents were compatible with this method and showed comparable yields. Finally, we show that C5-azido derivatives can help to avoid O , N -acyl protecting group migration which was observed in C5-NHAc analogs. [Display omitted] • Improved synthetic routes to access sialosides or DANA analogs with a C5-azide. • C5-azido DANA analogs avoid protecting group migrations found for N -Acyl intermediates. • Preparation of the C5-azido DANA in 6 steps and up to 80% yield. [ABSTRACT FROM AUTHOR]

Stage-specific embryonic antigens (SSEAs) are carbohydrate markers that have diverse roles in embryonic development. However, the exact roles of SSEAs remain unclear. To obtain mechanistic insights into their roles, we aimed to develop functionalized SSEA glycan analogs via chemical synthesis. Herein, we report a convergent synthetic approach for SSEA-3 and SSEA-4 analogs using readily available versatile building blocks. A key step, namely the stereoselective glycosylation of a common tetrasaccharide acceptor, was successfully achieved using a 4- O -Bn Gal donor for SSEA-3 and a Neu-Gal donor for SSEA-4, which were previously developed by our group. The obtained SSEA-3 and SSEA-4 glycans were further functionalized with biotin and deuterated lipid for applications in biological studies. Thus, the findings of this study will facilitate further research on SSEAs. [Display omitted] • A convergent synthetic approach for stage-specific embryonic antigens (SSEAs) 3 and 4 has been developed. • High utility of a 4- O -Bn Gal and a Neu-Gal donors has been revealed. • Biotinylated analogs and deuterated glycolipid analogs of SSEA-3 and 4 have been developed. [ABSTRACT FROM AUTHOR]

The immunobiological effectivity of glycolipids mimicking biosurfactants of the synthetic origin was followed up using macrophages cell line RAW264.7. These derivatives with different number of mannose units connected glycosidically or through triazole linker, and all having octyl aglycone, were evaluated with respect to their structure - immunomodulation activity relationship. This comparative study showed that the structural variations of the selected derivatives influenced the immunobiological cell behaviour as concerned pro-inflammatory TNF-α, IL-6, IL-1α, IL-17, IL-12 and anti-inflammatory IL-10 cytokines production and enhancement of RAW264.7 cell proliferation. The derivatives with mannose units linked through triazole linkers exerted in some cases stronger immunomodulative potency than (di)mannosides. On the other hand, a presence of triazole linker is a less favourable for an effective candidacidal activity as determined by in vitro using Candida albicans biofilm. The design of new defined immunomodulating formulas of the synthetic origin as possible antifungal agents and prospective participants in drug delivery systems may be of interest. [Display omitted] • Glycolipids mimetics with octyl aglycone and different number of mannose units • Immunobiological effectivity of selected glycolipids was determined • The impact of structure on immunomodulation activity was stressed • Glycolipids supported induction of RAW264.7 cell proliferation and cytokine release • The inhibition of Candida albicans biofilm by glycolipids was demonstrated [ABSTRACT FROM AUTHOR]

Chemical O -glycosylation is a key step for the synthesis of sugar-containing molecules such as glycolipids. However, traditional carbohydrate chemistry is characterized by extensive use of protective groups, resulting in laborious manipulations and poor atom economy. Here, we present a protecting-group-free glycosylation strategy employing dibenzyloxy-1,3,5-triazin-2-yl glycosides (DBT-glycosides) as glycosyl donors. The DBT-glycosyl donors could be prepared directly through an alkaline nucleophilic substitution from unprotected sugars in aqueous media. The O -glycosylation of alcohols by using DBT-glycosyl donors has been carried out under mild hydrogenolytic conditions, affording the corresponding alkyl glycosides stereo-selectively in good yields. [Display omitted] • A protecting group-free and stereoselective O -glycosylation method was described. • Glycosyl donors were prepared directly from unprotected sugars under water media. • Glycosylation reaction was performed under mild hydrogenolysis conditions. • Various sugar types (e.g., Glc, Gal, Man, GlcN, GlcNAc, etc) were screened. [ABSTRACT FROM AUTHOR]

In the attempt to create a delivery system for an alkali-cation stimulated drug release, a computational study was conducted, aiming for the evaluation of synthetic access towards glycolipid crown ethers analogs and their potential for coordination-induced changes of packing constraints for molecular assemblies. The results disfavor amide-linkages for the creation of macrocycles around the inter-glycosidic bond of a disaccharide. Conformational changes upon cation coordination of the macrocycle decrease the intersection area for easily accessible macrocycles based on lactose. This leads to shrinking intersection areas upon alkali complexation. Maltose-based analogs, on the other hand, exhibited the targeted increase of the glycolipid intersection area and, hence, may be considered as a promising resource. [Display omitted] • Cation templating for amide-linked macrocyclization on disaccharides is inefficient. • Force-field implied water solvation cannot cover hydrogen bonding interactions. • Hydrogen bonding at coordinated water ligands can be ignored. • The interface of 6,6′-macro-anellated alkyl lactosides shrinks upon complexation. • The interface of 6,6′-macro-anellated alkyl maltosides increases upon complexation. [ABSTRACT FROM AUTHOR]

Abstract The bacterium Pantoea ananatis was reported to produce glycolipid biosurfactants of unknown structures. Herein, we present the isolation and structural determination of ananatoside A, the main congener of a new family of 15-membered macrodilactone-containing glucolipids. The structure of ananatoside A was elucidated via chemical degradation and spectroscopic methods including 1D/2D NMR analysis, tandem MS/MS, GC-MS, HR-ESI-TOF-MS, MALDI-TOF-MS, and polarimetry. Computational methods were used to predict the most abundant conformers of ananatoside A. Graphical abstract Image 1 Highlights • A novel glycolipid biosurfactant was isolated from Pantoea ananatis. • Ananatoside A is an unprecedented 15-membered macrodilactone-containing glucolipid. • The structure of ananatoside A was elucidated by chemical and spectroscopic methods. [ABSTRACT FROM AUTHOR]

Abstract Two azide-terminated oligoethylene oxide spacered glycolipids have been synthesized, and their assembly behavior has been studied in comparison to the corresponding base surfactants. The results suggest potential of the Guerbet lactoside-based compound for targeted drug delivery, while a coiling of the ethylene oxide linker disfavors the application of the glucoside. Graphical abstract Azido-ethylene oxide spacered glycolipids as anchors for targeted vesicular drug delivery. Image 1 Highlights • Azido-terminated oligoethylene oxide was introduced at Guerbet glycosides. • Functionalization at O-4′ does not change phase behavior of Guerbet lactoside. • Intramolecular H-bonding causes coiling of oligoethylene oxide chain at glucose O-4. [ABSTRACT FROM AUTHOR]

Lactococcus cremoris and Lactococcus lactis are among the most extensively exploited species of lactic acid bacteria in dairy fermentations. The cell wall of lactococci, like other Gram-positive bacteria, possesses a thick peptidoglycan layer, which may incorporate cell wall polysaccharides (CWPS), wall teichoic acids (WTA), and/or lipoteichoic acids (LTA). In this study, we report the isolation, purification and structural analysis of the carbohydrate moieties of glycolipids (GL) and LTA of the L. cremoris model strain 3107. Chemical structures of these compounds were studied by chemical methods, NMR spectroscopy and positive and negative mode ESI MS. We found that the LTA of strain 3107 is composed of short chains of 1,3-polyglycerol phosphate (PGP), attached to O-6 of the non-reducing glucose of the kojibiose-Gro backbone of the glycolipid anchor. Extraction of cells with cold TCA afforded the detection of 1,3-glycerol phosphate chains randomly substituted at O-2 of glycerol by D -Ala. Unlike the LTA of L. lactis strains studied to date, the PGP backbone of the LTA of L. cremoris 3107 did not carry any glycosyl substitution. The deacylated glycolipid fraction contained the free kojibiose-Gro oligosaccharide, identical to the backbone of the GL anchor of LTA, and its shorter fragment α-Glc-1-Gro. These OS may have originated from the GL precursors of LTA biosynthesis. [Display omitted] • Lipoteichoic acid (LTA) from Lactococcus cremoris was studied. • LTA consists of polyglycerol phosphate, substituted with d -alanine. • Chain anchor consists of kojibiose-glycerol. • Structure is similar to Streptococcus and L. lactis LTA. [ABSTRACT FROM AUTHOR]

When it comes to the treatment of pathologies in which aberrant cell adhesion and extravasation from the bloodstream have been implicated, the selectins represent a central therapeutic target. In this context, the present work investigates the conformational landscape of two prototypes for the design of new antineoplasic and anti-inflammatory agents: the natural selectin ligand sialyl Lewis x and its mimetic GMI-1070. Accordingly, a series of unbiased molecular dynamics simulations at the microsecond scale using GROMOS 53A6 (GLYC), CHARMM36m and GLYCAM06 force fields were employed, together with ConfID, an analytical method for the characterization of conformational populations of small molecules. Our results for sialyl Lewis x are in agreement with and expand upon prior work. As for the mimetic, our results indicate that, in spite of its conformational restriction, GMI-1070's behavior in solution deviates from what had been proposed, highlighting thus some features that could be optimized, as the development of sialyl Lewis x mimetics continues, and new candidates emerge., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Hugo Verli reports financial support was provided by Federal University of Rio Grande do Sul Centre of Biotechnology. Hugo Verli reports financial support was provided by National Council for Scientific and Technological Development. Hugo Verli reports financial support was provided by Coordination of Higher Education Personnel Improvement. Hugo Verli reports financial support was provided by Foundation for Research Support of Rio Grande do Sul State. Hugo Verli reports financial support was provided by National Laboratory of Scientific Computing., (Copyright © 2023. Published by Elsevier Ltd.)

NKT cells are CD1d-restricted, glycolipid antigen-reactive, immunoregulatory T lymphocytes that can serve as a bridge between the innate and adaptive immunities. NKT cells have a wide range of therapeutic application in autoimmunity, transplant biology, infectious disease, cancer, and vaccinology. Rather than triggering “danger signal” and eliciting an innate immune response, αGalCer-based NKT-cell agonist act via a unique mechanism, recruiting NKT cells which play a T helper-like role even without peptide as Th epitope. Importantly, the non-polymorphism of CD1d render glycolipid a universal helper epitope, offering the potential to simplify the vaccine construct capable of eliciting consistent immune response in different individuals. This review details recent advances in the design of synthetic vaccines using NKT-cell agonist as adjuvant, highlighting the role of organic synthesis and conjugation technique to enhance the immunological actives and to simplify the vaccine constructs. [ABSTRACT FROM AUTHOR]

Low molecular weight gelators are important for the study of supramolecular chemistry and have useful applications for biomaterials. Glycomimetics that are easily accessible and have useful gelation properties are especially interesting molecules. In this research, nine per- O -acetyl lactosyl- and thirteen per- O -acetyl maltosyl triazole derivatives were synthesized and analyzed. Most of the maltosyl triazoles and one of the lactosyl derivatives were found to be effective molecular gelators. The supramolecular gels were characterized using rheology and optical microscopy and they exhibited morphologies ranging from fibers to planar sheets. The self-assembling properties of selected lactosyl and maltosyl triazole derivatives were studied using 1 H NMR spectroscopy at different temperatures. The NMR studies revealed that the triazole moiety in these compounds played an important role in the formation of the supramolecular assembly, but the sugar moiety configurations are more influential towards gelation. Naproxen and chloramphenicol were used as the model drugs to assess the potential of these compounds in drug delivery applications. A pH responsive gelator showed faster delivery of chloramphenicol at mild basic conditions than neutral conditions. The effective disaccharide triazole-based molecular gelators are useful for the preparation of advanced soft materials that have potential applications as matrix for immobilization of drugs or biomolecules. [ABSTRACT FROM AUTHOR]

The identification of immunoactive agents for clinical and mechanistic applications is a very active area of research. In this vein, analogues of the potent immunostimulant KRN 7000 with diverse cytokine profiles have attracted considerable attention. These compounds have been shown to activate iNKT cells via presentation by CD1d. Herein, we report on the synthesis and activity for four new C -glycosides of KRN 7000, 11-phenylundecanoyl and 11- p -fluorophenylundecanoyl derivatives of C -KRN 7000, 2,3-bis-epi- C -KRN 7000 and the reverse amide of C -KRN 7000. In mice, compared to C -KRN 7000, 2,3-bis-epi- C -KRN 7000 stimulated higher release of the anti-inflammatory cytokine IL-4 and lower release of the inflammatory cytokines IFN-γ and IL-12. The phenyl terminated alkanoyl and reverse amide analogues were inactive. These data suggest that structure activity effects for KRN 7000 are not necessarily additive and their use in the design of new analogues will require an improved understanding of how subtle structural changes impact on cytokine activity. [ABSTRACT FROM AUTHOR]

Human milk oligosaccharides (HMOs) are the third largest macromolecular component of breast milk and offer infants numerous health benefits, most of which stem from the development of a healthy microbiome. Characterization, quantification, and chemical derivatization of HMOs remains a frontier issue in glycobiology due to the challenge of isolating appreciable quantities of homogenous HMOs from breast milk. Herein, we report the synthesis of the human milk tetrasaccharide lacto- N -tetraose (LNT). LNT is ubiquitous in human breast milk as it is a core structure common to longer-chain HMOs and many glycolipids. [ABSTRACT FROM AUTHOR]

An efficient synthetic approach to tri-arabino di-mycolates, using structurally defined synthetic α-, keto and methoxy mycolic acids is described. [ABSTRACT FROM AUTHOR]

Glycolipid biosurfactants are of interest for various industry sectors. We report the synthesis and characterization of enantiopure poly-amido-saccharides (PASs) containing myristoyl (C14), palmitoyl (C16), or stearoyl (C18) terminal chain lengths as mimetics of glycolipid biosurfactants. These amphiphilic polymers are water soluble, adopt a helical secondary structure, decompose at temperatures greater than 240 °C, are non-cytotoxic, and self-assemble into nanostructures. Polymers containing the shorter hydrophilic chain lengths and the hydrophobic C14 chain exhibit the lowest surface tension among all polymers. [Display omitted] • Synthesis of enantiopure poly-amido-saccharides containing terminal fatty acids. • Demonstration of reduced surface tension and low cytotoxicity. • Formation of self-assembled nanostructures. • New class of biocompatible glycolipid mimetics. [ABSTRACT FROM AUTHOR]

A new series of hybrid surfactants comprising an imidazolium as a cation and a disaccharide as a non-ion were synthesized, and their aggregation behavior was also investigated. The synthetic approach used alkylation as an easily accessible route on an imidazole to attempt an economic production followed by coupling with bromoethyl lactoside to form lacto-imidazolium salts surfactants. The coupled surfactants were obtained in almost quantitative yield over several steps. The surfactant surface properties in aqueous media were investigated, including critical micelle concentration (CMC), Krafft temperature, and emulsion stability were studied. The CMC measurements of the alkyl imidazolium lactoside surfactants are significantly lower than normal imidazolium surfactants, while the emulsion investigations encourage the use of alkyl imidazolium lactoside surfactants owing to stabilized assemble behavior as good as APGs. [Display omitted] • Lactosides containing alkyl imidazolium are accessible cationic surfactants. • Alkyl imidazolium lactosides are quite water-soluble surfactants. • Alkyl imidazolium lactoside surfactants decrease the surface tension of water effectively. • Alkyl imidazolium lactoside surfactants show cubic and hexagonal H I phases. [ABSTRACT FROM AUTHOR]

Microbes produce a wide range of small molecule glycoconjugates that constitute unique molecular signatures. These molecules are recognized by a range of detection systems, triggering immune responses to microbial pathogens and commensals. The antigen-presenting molecules of the CD1 class, CD1a-d, capture lipidic molecules and present them to diverse and innate-like T cell populations including natural killer T cells and germline-encoded mycolyl reactive T cells. The antigen-presenting molecule MR1 captures vitamin B metabolites and presents them to mucosal associated invariant T cells. In both cases, recognition of the small molecule-antigen presenting molecule complexes occurs through T cell receptors on the surface of T lymphocytes. The pattern recognition receptors macrophage C-type lectin (MCL) and macrophage inducible C-type lectin (Mincle) receptors sense glycolipids and through signalling initiate cellular activation, shaping immune responses to peptide antigens, including the differentiation of naïve T cells into conventional effector T helper cells. In this review, we provide an overview of the diverse structures of immunogenic lipidic molecules and vitamin B metabolites and their recognition by select systems of the immune system. Future advances in our understanding of the roles of such molecules in innate and adaptive immune responses will require the coordinated efforts of synthetic and natural products chemists, immunologists and biologists. [ABSTRACT FROM AUTHOR]

Glycolipids, consisting of a carbohydrate moiety linked to fatty acids, are microbial surface active compounds produced by various microorganisms. They are characterized by highly structural diversity and have the ability to decrease the surface and interfacial tension at the surface and interface respectively. Rhamnolipids, trehalolipids, mannosylerythritol-lipids and cellobiose lipids are among the most popular glycolipids. Moreover, their ability to form pores and destabilize biological membrane permits their use in biomedicine as antibacterial, antifungal and hemolytic agents. Their antiviral and antitumor effects enable their use in pharmaceutic as therapeutic agents. Also, glycolipids can inhibit the bioadhesion of pathogenic bacteria enabling their use as anti-adhesive agents and for disruption of biofilm formation and can be used in cosmetic industry. Moreover, they have great potential application in industry as detergents, wetting agents and for flotation. Furthermore, glycolipids can act at the surface and can modulate enzyme activity permitting the enhancement or the inhibition of the activity of certain enzymes. [ABSTRACT FROM AUTHOR]

The iodocyclization of homoallylic trichloroacetimidates derived from α- C -allyl galactoside were investigated. In line with the stereochemical trend observed for less substituted non-glycosylated frameworks, E and Z substrates delivered stereoselectively the 1,3- anti and 1,3- syn amino alcohol motifs, respectively. These products are advanced precursors to C -glycosides of the potent immunostimulatory glycolipid KRN7000. [ABSTRACT FROM AUTHOR]

A series of glycolipid crown ether analogs was prepared by bis-propargylation of lauryl glycoside followed by subsequent click-coupling with ethylene glycol-based diazides. The triazole-linked macrocycles were obtained in remarkable high yields. While the surfactant assembly was affected by presence of sodium ions, suggesting the formation of complexes, no ion-selectivity was observed for the macrocylic ligands. Computational studies suggest a low but significant cation-binding activity of the macrocycle, involving coordination at both oxygen and nitrogen atoms. [ABSTRACT FROM AUTHOR]

Glycolipids are ubiquitous and biologically important molecules and are involved in diverse biological functions and exhibit biosurfactant applications due to their surface-active and biodegradability properties. Despite showing a wide range of biological functions, not enough commercial exploitation has been taken place. Possible reasons for this could be the lack of focus or commercially viable processes for isolation/purification, as these glycolipids are found to be complex mixtures in their respective natural sources. Keeping these complexities in view, in this review, we focused on natural occurrences, including plants, marine micro algae, microorganisms, and salient features of various chemical methods, including glycosylation methods for the synthesis of different types of glycolipids. Further, this review significantly summarises the biological evaluation of a diverse class of glycolipids isolated and/or synthesized either by partial or total synthesis. [Display omitted] • Microbial, plant, animal, and synthetic sources of Glycolipids. • Various glycosyl donors. • Synthetic methods discussion for all types of glycolipids. • Biological activities of glycolipids. [ABSTRACT FROM AUTHOR]

Highlights: [•] Psedozyma aphidis ZJUDM34 has the potential to produce mannosylerythritol lipid-A. [•] New types of MEL-A homologs were isolated and identified. [•] MEL-A homologs were found to have long unsaturated fatty acid chains. [•] Medium with manganese ions is conducive to MEL-A formation. [Copyright &y& Elsevier]

Highlights: [•] Synthesis of 6″-deoxy-6″-thio trisaccharide propargyl glycosides. [•] Click chemistry with 1-azidododecane and 1-azidooctadecane. [•] Zemplén deprotection gave disulfides of 6″-thio glycolipid trisaccharides. [•] Mono- and bilayers on Au(111) surface were assessed by differential capacitance. [•] A monosaccharide glycolipid tethered an artificial bilayer lipid membrane on Au(111). [ABSTRACT FROM AUTHOR]

Highlights: [•] Glycolipids play an important role in the immune response. [•] Trehalose dimycolates, lipoteichoic acids and α-galactosyl ceramide are discussed. [•] Synthesis allows for the development of molecular tools. [•] Molecular tools allow for valuable insight into biological activity. [Copyright &y& Elsevier]

iNKT cells are a special type of T cell that acts as a link between the innate and adaptive immune systems, with the capacity to stimulate a wide range of cell types. The glycolipid α-galactosylceramide (αGC) is a robust agonist of iNKT cells and induces the secretion of Th1- and Th2-type cytokines. αGC and its analogs are widely used as adjuvants to enhance immune responses against viral, parasitic, and bacterial pathogens. This review first discusses the challenges of using free αGC as a vaccine adjuvant to treat infectious diseases. We next present strategies to realize the potential of the adjuvant effect of iNKT cell glycolipids, including (1) the use of Th1- or Th2-biasing αGC analogs, (2) covalent conjugation of glycolipid with antigen, (3) particulate vehicle-assisted delivery of glycolipid, (4) glycolipid-loaded cellular systems, (5) glycolipid combination with other immunostimulants, and (6) usage as mucosal adjuvants. Finally, we discuss future approaches for the development of iNKT cell agonists used as vaccine adjuvants against infectious diseases. [Display omitted] • iNKT cell glycolipid agonists offer a unique and novel approach to improve immunotherapies and vaccination. • Bioconjugation and formulation sciences could maximize the adjuvant potential of the α-GalCer glycolipid. • iNKT cell-stimulating glycolipids represent a new generation mucosal adjuvant. [ABSTRACT FROM AUTHOR]

Lipidated derivatives of the natural product brartemicin show much promise as vaccine adjuvants due to their ability to signal through the Macrophage Inducible C-type Lectin (Mincle). We synthesised three lipophilic amide-linked brartemicin derivatives and compared their agonist activity to that of their ester-linked counterparts in vitro. We demonstrate that the brartemicin amide derivatives activate bone-marrow-derived macrophages (BMDMs) in a Mincle-dependent manner, as evidenced by the production of the pro-inflammatory cytokine IL-1β in wildtype but not Mincle-/- cells. The amide derivatives showed activity that was as good as, if not better than, their ester counterparts. Two of the amide derivatives, but none of the ester-derivatives, also led to the production of IL-1β by human-derived monocytes. As the production of IL-1β is a good indicator of vaccine adjuvanticity potential, these findings suggest that amide-linked brartemicin derivatives show particular promise as vaccine adjuvants. [Display omitted] • Three lipophilic amide-linked brartemicin derivatives were synthesised. • The amides were as good or better agonists than their ester counterparts. • Two of the amide derivatives also led to the production of IL-1β by monocytes. [ABSTRACT FROM AUTHOR]

Abstract: Carbohydrates, in more biologically oriented areas referred to as glycans, constitute one of the four groups of biomolecules. The glycans, often present as glycoproteins or glycolipids, form highly complex structures. In mammals ten monosaccharides are utilized in building glycoconjugates in the form of oligo- (up to about a dozen monomers) and polysaccharides. Subsequent modifications and additions create a large number of different compounds. In bacteria, more than a hundred monosaccharides have been reported to be constituents of lipopolysaccharides, capsular polysaccharides, and exopolysaccharides. Thus, the number of polysaccharide structures possible to create is huge. NMR spectroscopy plays an essential part in elucidating the primary structure, that is, monosaccharide identity and ring size, anomeric configuration, linkage position, and sequence, of the sugar residues. The structural studies may also employ computational approaches for NMR chemical shift predictions (CASPER program). Once the components and sequence of sugar residues have been unraveled, the three-dimensional arrangement of the sugar residues relative to each other (conformation), their flexibility (transitions between and populations of conformational states), together with the dynamics (timescales) should be addressed. To shed light on these aspects we have utilized a combination of experimental liquid state NMR techniques together with molecular dynamics simulations. For the latter a molecular mechanics force field such as our CHARMM-based PARM22/SU01 has been used. The experimental NMR parameters acquired are typically 1H,1H cross-relaxation rates (related to NOEs), 3 J CH and 3 J CC trans-glycosidic coupling constants and 1H,13C- and 1H,1H-residual dipolar couplings. At a glycosidic linkage two torsion angles ϕ and ψ are defined and for 6-substituted residues also the ω torsion angle is required. Major conformers can be identified for which highly populated states are present. Thus, in many cases a well-defined albeit not rigid structure can be identified. However, on longer timescales, oligosaccharides must be considered as highly flexible molecules since also anti-conformations have been shown to exist with H–C–O–C torsion angles of ∼180°, compared to syn-conformations in which the protons at the carbon atoms forming the glycosidic linkage are in close proximity. The accessible conformational space governs possible interactions with proteins and both minor changes and significant alterations occur for the oligosaccharides in these interaction processes. Transferred NOE NMR experiments give information on the conformation of the glycan ligand when bound to the proteins whereas saturation transfer difference NMR experiments report on the carbohydrate part in contact with the protein. It is anticipated that the subtle differences in conformational preferences for glycan structures facilitate a means to regulate biochemical processes in different environments. Further developments in the analysis of glycan structure and in particular its role in interactions with other molecules, will lead to clarifications of the importance of structure in biochemical regulation processes essential to health and disease. [Copyright &y& Elsevier]

Highlights: [•] Staudinger reaction enables synthesis of amide linked glyco-glycerolipid analogs. [•] Steric hindrance can lead to Staudinger-based cyclization of 1,3-diazides. [•] Amide analogs of glyco-glycero lipids exhibit very high Krafft temperatures. [Copyright &y& Elsevier]

Abstract: O-Glycan is a major oligosaccharide expressed on the surface of eukaryotic cells that plays a role in immune responses via cell–protein and cell–cell interaction. Unlike N-glycan and glycolipid-derived glycan, O-glycans have not been previously reported in pig organs. Here, we report the first instance of the identification of α1,3 galactosylated O-glycans from pig kidney and endothelial cells by using MALDI-TOF MS and nano-ESI MS/MS. The MALDI profile showed 28 O-glycans from miniature pig kidney and 18 O-glycans from pig endothelial cells. Among them, three potential α-galactosylated glycans considered as immunogenic antigens were identified by CID using ESI-MS/MS; Hexα1,3Hex-HexNAc-HexNAc, Hexα1,3Hex-Hex-HexNAc-HexNAc, and Hexα1,3Hex-Hex-Hex-Hex-HexNAc. This structural information on glycans will provide significant information to clinical studies regarding immune rejection responses induced by carbohydrate antigens during xenotransplantation. [Copyright &y& Elsevier]

Abstract: To date, the structures of the glycolipids from Lactobacillus plantarum, a commonly used beneficial probiotic, have not been conclusively assigned. Herein, we report for the first time, the full characterisation of the four principal glycolipids of the L. plantarum cell wall using sugar, linkage and FAME analysis, as well as ESI-MS/MS and 1D- and 2D-NMR spectroscopy, and assign the major glycolipids as being: α-d-Glcp-diglyceride, α-d-Galp-(1→2)-α-d-Glcp-diglyceride, β-d-Glcp-(1→6)-α-d-Galp-(1→2)-6-O-acyl-α-d-Glcp-diglyceride and β-d-Glcp-(1→6)-α-d-Galp-(1→2)-α-d-Glcp-diglyceride. [Copyright &y& Elsevier]

Abstract: A variety of trehalose glycolipids have been isolated from natural sources, and several of these glycolipids exhibit important biological properties. These molecules also represent challenging synthetic targets due to their highly amphiphilic character, their large number of functional groups and additional chiral centres. This review highlights some of the recent advances made in the synthesis of trehalose glycolipids, and their associated biological activities. [Copyright &y& Elsevier]

Abstract: A glycoglycerolipid 1a isolated from a marine alga showed inhibition to Myt1 kinase with IC50 of 0.12μg/mL. We synthesized 1a and its seven analogues (1b–h) in an efficient method with high stereoselectivity. The process employed trichloroacetimidate donor 4b at low substrate concentration to achieve high α-selectivity (α/β=33:1) in glycosylation reaction. The present synthesis provided various acyl derivatives required for the study on the structure–activity relationship later. [Copyright &y& Elsevier]

Abstract: Triazolyl glycolipid derivatives constructed via CuI-catalyzed azide-alkyne 1,3-dipolar cycloaddition reaction (Cue-AAC) represent a new range of carbohydrate-based scaffolds for use in many fields of the chemical research. Here the surface adsorptive ability of series of our previously prepared C1- or C6-triazole linked gluco- and galactolipid derivatives for mild steel in 1M HCl was studied via electrochemical impedance spectroscopy (EIS). Results indicated that these monosaccharide–fatty acid conjugates are weak inhibitors against HCl corrosion for mild steel. Moreover, some newly synthesized triazolyl disaccharide (maltose)–fatty alcohol conjugates failed to display enhanced activity, meaning that the structural enlargement of the sugar moiety does not favor the iron surface adsorption. However, a bis-triazolyl glycolipid derivative, which was realized by introducing a benzenesulfonamide group via Cue-AAC to the C6-position of a C1-triazolyl glucolipid analog, eventually showed significantly improved adsorptive potency compared to that of its former counterparts. The corrosion inhibitive modality of this compound for mild steel in HCl was subsequently studied via potentiodynamic polarization and thermodynamic calculations. [Copyright &y& Elsevier]

Abstract: Simplexide is a glycolipid of marine origin, endowed with immunological properties, composed of a long chain secondary alcohol glycosylated by an α-d-glucosyl-(1→4)-β-d-galactosyl disaccharide residue. Herein we describe the preparation of a fluorescent derivative of simplexide, labeled at position 6 of the distal glucose with a dansyl group, as a probe for future studies on the mechanism by which simplexide affects the immune system. Fluorescent simplexide was prepared from a 6″-amino functionalized compound, which in turn was obtained through a highly efficient glycosylation between the preformed activated disaccharide and the long chain secondary alcohol 18-pentatriacontanol. [Copyright &y& Elsevier]

Abstract: Sophorolipids are a group of O-acylsophorose-based biosurfactants produced by several yeasts of the Starmerella clade. The known sophorolipids are typically partially acetylated 2-O-β-d-glucopyranosyl-d-glucopyranose (sophorose) O-β-glycosidically linked to 17-l-hydroxy-Δ9-octadecenoic acid, where the acyl carboxyl group often forms a 4″-lactone to the terminal glucosyl residue. In a recent MALDI-TOFMS-based screen for sophorolipid-producing yeasts we identified a new species, Candida sp. NRRL Y-27208, that produces significant amounts of novel sophorolipids. This paper describes the structural characterization of these new compounds, using carbohydrate and lipid analysis, mass spectrometry, and NMR spectroscopy. Unlike those reported previously, the NRRL Y-27208 sophorolipids contain an ω-hydroxy-linked acyl group (typically 18-hydroxy-Δ9-octadecenoate), and occur predominantly in a non-lactone, anionic form. In addition, 17 dimeric and trimeric sophoroses were identified by MALDI-TOFMS from this strain. The surfactant-like properties of these sophorolipids have value as potential replacements for petroleum-based detergents and emulsifiers. [Copyright &y& Elsevier]

Abstract: Anomers and epimers α- and β-gluco and -galactosides are expected to behave differently. However, recent results on a series of Guerbet glycosides have indicated similar liquid crystal clearing temperatures for pure β-glucosides and the corresponding α-galactosides. This observation has led to speculation on similarities in the self-assembly interactions between the two systems, attributed to the trans-configuration of the 4-OH group and the hydrophobic aglycon. Previous simulations on related bilayers systems support this hypothesis, by relating this clearing transition temperature to intralayer (sugar–sugar) hydrogen bonding. In order to confirm the hypothesis, the comparison was expanded to include the cis-configurated pair, that is, α-gluco/β-galactoside. A set of α-configurated Guerbet glucosides as well as octyl α-galactoside were prepared and their thermotropic phase behavior studied. The data obtained enabled a complete comparison of the isomers of interest. While the results in general are in line with a pairing of the stereo-isomers according to the indicated cis/trans-configuration, differences within the pairs can be explained based on the direction of hydrogen bonds from a simple modeling study. [Copyright &y& Elsevier]

Abstract: Bacteria belonging to the genus Aeromonas are Gram-negative mesophilic and essentially ubiquitous in the microbial biosphere; moreover they are considered very important pathogens in fish and responsible for a great variety of human infections. The virulence of Gram-negative bacteria is often associated with the structure of lipopolysaccharides, which consist of three regions covalently linked: the glycolipid (lipid A), the oligosaccharide region (core region) and the O-specific polysaccharide (O-chain, O-antigen). The O-chain region seems to play an important role in host-pathogen interaction. In the case of Aeromonas hydrophila the majority of pathogenic strains belongs to serogroups O:11, O:16, O:18 and O:34. In this paper, we report the complete structure of the O-chain of A. hydrophila strain A19 (serogroup O:14), a pathogenic strain isolated from European eels, which showed high virulence when tested in trout or mice. Dried cells were extracted by the PCP (phenol/chloroform/petroleum ether) method obtaining the lipopolysaccharide. After mild acid hydrolysis the lipid A was removed by centrifugation and the obtained polysaccharide was fully characterized by means of chemical analysis and one- and two-dimensional NMR spectroscopy. All the data collected are directed towards the following structure:▪ [Copyright &y& Elsevier]

Abstract: The title compound containing dihydroceramide as a ligand for CD1d was accomplished using the mannosyl, glucosaminyl, and fucosyl donors, and a sphinganine analogue, as suitable building blocks. The 2-O-unprotected mannosyl donor was coupled effectively with the sphinganine analog to afford the mannnosyl sphinganine derivative. The coupling of the glucosaminyl donor with the mannnosyl sphinganine acceptor required triflic acid as a promoter and the promoter change to silver triflate led to the undesired glycal production. The reduction of azide group using Zn powder was the key process, in which the amount of acetic acid was restricted to avoid the benzoyl migration and N-trichloroacetyl deprotection. The trisaccharide glycolipid was sulfonated at the 3-position of fucose moiety. [Copyright &y& Elsevier]

Abstract: A class of glycolipopeptides for use as building blocks for a new type of dynamic combinatorial library is reported. The members of the library consist of a variable carbohydrate moiety, coded amino acids, and lipoamino acids in order to convert them into amphiphiles. Glycolipopeptidic amphiphiles interact through non-covalent bonding when mixed together in aqueous phase and form micelles in dynamic close-packed fluid mosaic arrays. The head groups of amphiphiles are exposed on the micelle surface, providing entities which could be screened in biological assays to find the most potent combination of building blocks in order to identify new bioactive carbohydrate ligands. [Copyright &y& Elsevier]

Abstract: Borrelia burgdorferi is the etiological agent for Lyme disease (LD), the most common vector borne disease in the United States. There is no human vaccine against LD currently available. Our approach to a vaccine is based on its surface-exposed glycolipids. One group of these glycolipids termed BBGL-2 consists of 1,2-di-O-acyl-3-O-(α-d-galactopyranosyl)-sn-glycerol congeners having palmitic, oleic, stearic, linoleic, and myristic acids. In order to delineate the immunodominant region(s) of the BBGL-2 components, we embarked on a synthetic project to provide available structurally defined, homogeneous analogs of BBGL-2 that might help identify the best vaccine candidate. The antigenicity of the synthetic glycolipids was examined by dot-blot analysis using mice sera obtained by immunization with killed B. burgdorferi cells, with native BBGL-2 in complete Freund’s adjuvant, as well as sera obtained from patients with Lyme disease. We found that the presence of two acyl groups in the glycerol moiety was essential for antigenicity. At least one of these groups must be an oleoyl moiety. Neither the anomeric configuration of the galactose nor the configuration of the glycerol at C-2 was a decisive factor. Based on these findings we designed an ‘unnatural’ BBGL-2 analog having the structure 3-O-(β-d-galactopyranosyl)-1,2-di-O-oleoyl-d l-glycerol which is easier and less expensive to synthesize than the other BBGL-2 congeners prepared in this study. This substance proved to be antigenic and is considered a candidate vaccine for Lyme disease. [Copyright &y& Elsevier]

Abstract: 1- or 6-Triazologluco- and galactolipid derivatives bearing a lipid chain length of 16 carbons were efficiently constructed via click chemistry. The differentiation in their surface pressure-molecular area (π–A) isotherms first implies that these structurally and configurationally diverse amphiphiles adopt different distribution manner at air–water interfaces. The Langmuir–Blodgett (LB) films of the synthesized glycoconjugates on mica surface were subsequently prepared and visualized via atomic force microscopy (AFM), which exhibited diverse topographies and possess different contact angles with water. These data further suggest that the structural variation as well as epimeric identity of triazologlycolipids may result in their distinct interfacial behaviors at the air–solid interface. Furthermore, the addition of increasing amounts of 1-triazologalactolipid 2 to poly-diacetylene (PDA) was determined to impact the π–A isotherm of the latter, prompting us to further fabricate new colorimetrically detectable mixed-type vesicles containing triazologlycolipids for biochemical studies. [Copyright &y& Elsevier]

Abstract: A highly efficient synthesis of the biologically important fluorescent probe dansyl α-GalCer is presented. Key in our strategy is the incorporation of the fluorescent dansyl group at an early stage in the synthesis to facilitate in the monitoring and purification of intermediates via TLC and flash column chromatography, respectively, and the use of a high yielding α-selective glycosylation reaction between the phytosphingosine lipid and a galactosyl iodide donor. The ability of dansyl α-GalCer to activate iNKT cells and to serve as a fluorescent marker for the uptake of glycolipid by dendritic cells is also presented. [Copyright &y& Elsevier]

Abstract: A series of crown ethers involving lauryl glucoside were synthesized and their assembly behavior in water was studied. The synthesis applied a simple protection scheme based on benzylidenation for the glycolipid, and cation templating for the macrocycle. A sequential build-up of the crown ether by bis-hydroxylethylation of the glucoside followed by reaction with di-, tri-, or tetraethylene glycol ditosylate provided better yields of the macrocycle compared to a single step cyclization with tetraethylene glycole ditosylate. The macrocycles containing up to six oxygens showed significantly higher affinity for sodium than for potassium, while more effective potassium complexation was found for the 21-crown-7 compound. The ion binding affinity leads to a slight but significant increase of the CMC of the crown ether containing surfactant in water upon the addition of sodium electrolyte. [Copyright &y& Elsevier]

Abstract: Halomonas stevensii is a Gram-negative, pathogenic, moderately halophilic bacterium isolated from the blood of a renal care patient. It optimally grows at 30–35°C at pH 8–9 and at a sea salt concentration ranging from 3.0% to 7.5%. Gram-negative bacterial infections are closely associated with the presence of the lipopolysaccharides (LPSs) on the outer membrane. These molecules consist of three regions covalently linked: the glycolipid (lipid A), the oligosaccharide region (core region), and the O-specific polysaccharide (O-chain, O-antigen). O-antigen seems to play an important role in the colonization step (adherence) and the ability to bypass host defense mechanisms. For this reason the structure elucidation of the O-chain repeating unit is important to improve knowledge about the role of LPS in the host-pathogen interaction. In this paper, we report the complete structure of the O-chain from the LPS of H. stevensii. The bacterial cells were cultivated and LPS was extracted by the PCP (phenol–chloroform–petroleum ether) method. After mild acid hydrolysis, the lipid A was removed by centrifugation and the obtained polysaccharide was analyzed by means of chemical analysis and one- and two-dimensional NMR spectroscopy giving the following structure:▪ [ABSTRACT FROM AUTHOR]