Synthesis of a Monophosphoryl Derivative of Escherichia coli Lipid A and Its Efficient Coupling to a Tumor‐Associated Carbohydrate Antigen

Monophosphoryl lipid A is a safe and potent immunostimulant and vaccine adjuvant, which is potentially useful for the development of effective carbohydrate‐based conjugate vaccines. This paper presents a convergent and efficient synthesis of a monophosphoryl derivative of E. coli lipid A that has an alkyne functionality at the reducing end, which is suitable for coupling with various molecules. The coupling of this derivative to an N‐modified analogue of tumor‐associated antigen GM3 through click chemistry is also presented.     

Synthesis of the core structure of the lipoteichoic acid of Streptococcus pneumoniae

Streptococcus pneumoniae LTA is a highly complex glycophospholipid that consists of nine carbohydrate residues: three glucose, two galactosamine and two 2‐acetamino‐4‐amino‐2,4,6‐trideoxygalactose (AATDgal) residues that are each differently linked, one ribitol and one diacylated glycerol (DAG) residue. Suitable building blocks for the glucose and the AATDgal residues were designed and their synthesis is described in this paper. These building blocks permitted the successful synthesis of the core structure Glcβ(1‐3)AATDgalβ(1‐3)Glcα(1‐O)DAG in a suitably protected form for further chain extension ( 1 b , 1 c ) and as unprotected glycolipid ( 1 a ) that was employed in biological studies. These studies revealed that 1 a as well as 1 lead to interleukin‐8 release, however not via TLR2 or TLR4 as receptor.     

Preactivation‐Based,One‐Pot Combinatorial Synthesis of Heparin‐like Hexasaccharides for the Analysis of Heparin–Protein Interactions

Heparin (HP) and heparan sulfate (HS) play important roles in many biological events. Increasing evidence has shown that the biological functions of HP and HS can be critically dependent upon their precise structures, including the position of the iduronic acids and sulfation patterns. However, unraveling the HP code has been extremely challenging due to the enormous structural variations. To overcome this hurdle, we investigated the possibility of assembling a library of HP/HS oligosaccharides using a preactivation‐based, one‐pot glycosylation method. A major challenge in HP/HS oligosaccharide synthesis is stereoselectivity in the formation of the cis‐1,4‐linkages between glucosamine and the uronic acid. Through screening, suitable protective groups were identified on the matching glycosyl donor and acceptor, leading to stereospecific formation of both the cis‐1,4‐ and trans‐1,4‐linkages present in HP. The protective group chemistry designed was also very flexible. From two advanced thioglycosyl disaccharide intermediates, all of the required disaccharide modules for library preparation could be generated in a divergent manner, which greatly simplified building‐block preparation. Furthermore, the reactivity‐independent nature of the preactivation‐based, one‐pot approach enabled us to mix the building blocks. This allowed rapid assembly of twelve HP/HS hexasaccharides with systematically varied and precisely controlled backbone structures in a combinatorial fashion. The speed and the high yields achieved in glycoassembly without the need to use a large excess of building blocks highlighted the advantages of our approach, which can be of general use to facilitate the study of HP/HS biology. As a proof of principle, this panel of hexasaccharides was used to probe the effect of backbone sequence on binding with the fibroblast growth factor‐2 (FGF‐2). A trisaccharide sequence of 2‐O‐sulfated iduronic acid flanked by N‐sulfated glucosamines was identified to be the minimum binding motif and N‐sulfation was found to be critical. This provides useful information for further development of more potent compounds towards FGF‐2 binding, which can have potential applications in wound healing and anticancer therapy.     

Highly stereoselective De-Novo synthesis of protected 2-amino-3-C-methyl-2,3-dideoxy-d-altrose

A new strategy for the stereoselective synthesis of 2-amino-2-deoxy-aldoses is described. Therefore epoxy carbamates are reacted with isocyanates to furnish urethanes, which will form the title compounds with high diastereoselectivities under basic conditions and O,O-migration of the carbamoyl group.     

Synthesis of Benzaldehyde‐Functionalized Glycans: A Novel Approach Towards Glyco‐SAMs as a Tool for Surface Plasmon Resonance Studies

In recent years the interest in tools for investigating carbohydrate–protein (CPI) and carbohydrate‐carbohydrate interactions (CCI) has increased significantly. For the investigation of CPI and CCI, several techniques employing different linking methods are available. Surface plasmon resonance (SPR) imaging is a most appropriate tool for analyzing the formation of self‐assembled monolayers (SAM) of carbohydrate derivatives, which can mimic the glycocalyx. In contrast to the SPR imaging methods used previously to analyze CPI and CCI, the novel approach reported herein allows a facile and rapid synthesis of linker spacers and carbohydrate derivatives and enhances the binding event by controlling the amount and orientation of ligand. For immobilization on biorepulsive amino‐functionalized SPR chips by reductive amination, diverse aldehyde‐functionalized glycan structures (glucose, galactose, mannose, glucosamine, cellobiose, lactose, and lactosamine) have been synthesized in several facile steps that include olefin metathesis. Effective immobilization and the first binding studies are presented for the lectin concanavalin A.     

The synthesis of Leishmania major phosphoglycan fragments

The triglycosyl monophosphate 1, heptaglycosyl triphosphates 2 and 3, and octaglycosyl triphosphate 4, which are fragments of the phosphoglycan part of Leishmania major lipo- and proteo-phosphoglycans have been prepared using di- and tri-saccharide H-phosphonates for construction of the phosphodiester bridges.     

Characterization of the Core Oligosaccharide and the O‐Antigen Biological Repeating Unit from Halomonas stevensii Lipopolysaccharide: The First Case of O‐Antigen Linked to the Inner Core

A novel core structure among bacterial lipopolysaccharides (LPS) that belong to the genus Halomonas has been characterized. H. stevensii is a moderately halophilic microorganism, as are the majority of the Halomonadaceae. It brought to light the pathogenic potential of this genus. On account of their role in immune system elicitation, elucidation of LPS structure is the mandatory starting point for a deeper understanding of the interaction mechanisms between host and pathogen. In this paper we report the structure of the complete saccharidic portion of the LPS from H. stevensii. In contrast to the finding that the O‐antigen is usually covalently linked to the outer core oligosaccharide, we could demonstrate that the O‐polysaccharide of H. stevensii is linked to the inner core of an LPS. By means of high‐performance anion‐exchange chromatography with pulsed amperometric detection we were able to isolate the core decasaccharide as well as a tridecasaccharide constituted by the core region plus one O‐repeating unit after alkaline degradation of the LPS. The structure was elucidated by one‐ and two‐dimensional NMR spectroscopy, ESI Fourier transform ion cyclotron resonance (FT‐ICR) mass spectrometry, and chemical analysis.