Highly Efficient Synthesis of Multiantennary Bisected N‐glycans Based on Imidates

Mönnich, Manuel; Eller, Steffen; Karagiannis, Theodoros; Perkams, Lukas; Luber, Thomas; Ott, Dimitri; Niemietz, Mathäus; Hoffman, Joanna; Walcher, Janika; Berger, Lukas; Pischl, Matthias; Weishaupt, Markus; Wirkner, Cathrin; Lichtenstein, Rachel G.; Unverzagt, Carlo

doi:10.1002/anie.201604190

Cited by 38 publications

(44 citation statements)

References 61 publications

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“…The N‐TFAc‐protected building blocks B – E efficiently provide N‐glycans with an optional bisecting modification ( G1 – G8 ) . We thus intended to combine the latter approach with the core trisaccharide A functionalized for the late introduction of α1,6‐linked fucose .…”

Section: Methodsmentioning

confidence: 99%

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

et al. 2018

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The occurrence of α1,6‐linked core fucose on the N‐glycans of mammalian glycoproteins is involved in tumor progression and reduces the bioactivity of antibodies in antibody‐dependent cell‐mediated cytotoxicity (ADCC). Since core‐fucosylated N‐glycans are difficult to isolate from natural sources, only chemical or enzymatic synthesis can provide the desired compounds for biological studies. A general drawback of chemical α‐fucosylation is that the chemical assembly of α1,6‐linked fucosides is not stereospecific. A robust and general method for the α‐selective fucosylation of acceptors with primary hydroxy groups in α/β ratios exceeding 99:1 was developed. The high selectivities result from the interplay of an optimized protecting group pattern of the fucosyl donors in combination with the activation principle and the reaction conditions. Selective deprotection yielded versatile azides of all mammalian complex‐type core‐fucosylated N‐glycans with 2‐4 antennae and optional bisecting GlcNAc.

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Section: Methodsmentioning

confidence: 99%

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

et al. 2018

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“…Aspartylation with the complex‐type nonasaccharide amine 8 b proceeded in 29 % yield. The glycosylamine 8 c required for the main glycoform of Sap D was synthesized from the three building blocks 16 , 17 and 18 using double regio‐ and stereoselective glycosylation protocols followed by an NBS mediated selective deprotection to the anomeric azide and reduction to 8 c (10 steps total, supporting information). Benzoate protected mannosyl donor 17 reacted with the core trisaccharide 16 with high α1,3‐selectivity accompanied by some double glycosylation and low orthoester formation.…”

Section: Methodsmentioning

confidence: 99%

Synthetic Glycoforms Reveal Carbohydrate‐Dependent Bioactivity of Human Saposin D

et al. 2017

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The main glycoforms of the hydrophobic lysosomal glycoprotein saposin D( SapD) were synthesized by native chemical ligation. An approach for the challenging solid-phase synthesis of the fragments was developed. Three SapD glycoforms were obtained following ag eneral and robust refolding and purification protocol. Acrystal structure of one glycoform confirmed its native structure and disulfide pattern. Functional assays revealed that the lipid-binding properties of three SapD glycoforms are highly affected by the single sugar moiety of SapD showing ad ependency of the size and the type of Nglycan.Supportinginformation and the ORCID identification number(s) for the author(s) of this article can be found under http://dx.

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“…7,8 Despite that most complex N -glycans have asymmetrical architectures, synthetic efforts have almost exclusively focused on the preparation of incomplete or symmetrically branched structures. 9 …”

Section: Introductionmentioning

confidence: 99%

Chemoenzymatic Approach for the Preparation of Asymmetric Bi-, Tri-, and Tetra-Antennary N-Glycans from a Common Precursor

Gagarinov

Li²,

Toraño

et al. 2017

J. Am. Chem. Soc.

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Progress in glycoscience is hampered by a lack of well-defined complex oligosaccharide standards that are needed to fabricate the next generation of microarrays, to develop analytical protocols to determine exact structures of isolated glycans, and to elucidate pathways of glycan biosynthesis. We describe here a chemoenzymatic methodology that makes it possible, for the first time, to prepare any bi-, tri-, and tetra-antennary asymmetric N-glycan from a single precursor. It is based on the chemical synthesis of a tetra-antennary glycan that has N-acetylglucosamine (GlcNAc), N-acetyllactosamine (LacNAc), and unnatural Galα(1,4)-GlcNAc and Manβ(1,4)-GlcNAc appendages. Mammalian glycosyltransferases recognize only the terminal LacNAc moiety as a substrate, and thus this structure can be uniquely extended. Next, the β-GlcNAc terminating antenna can be converted into LacNAc by galactosylation and can then be enzymatically modified into a complex structure. The unnatural α-Gal and β-Man terminating antennae can sequentially be decaged by an appropriate glycosidase to liberate a terminal β-GlcNAc moiety, which can be converted into LacNAc and then elaborated by a panel of glycosyltransferases. Asymmetric bi- and triantennary glycans could be obtained by removal of a terminal β-GlcNAc moiety by treatment with β-N-acetylglucosaminidase and selective extension of the other arms. The power of the methodology is demonstrated by the preparation of an asymmetric tetra-antennary N-glycan found in human breast carcinoma tissue, which represents the most complex N-glycan ever synthesized. Multistage mass spectrometry of the two isomeric triantennary glycans uncovered unique fragment ions that will facilitate identification of exact structures of glycans in biological samples.

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Highly Efficient Synthesis of Multiantennary Bisected N‐glycans Based on Imidates

Cited by 38 publications

References 61 publications

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

A Single Route to Mammalian N‐Glycans Substituted with Core Fucose and Bisecting GlcNAc

Synthetic Glycoforms Reveal Carbohydrate‐Dependent Bioactivity of Human Saposin D

Chemoenzymatic Approach for the Preparation of Asymmetric Bi-, Tri-, and Tetra-Antennary N-Glycans from a Common Precursor

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