Making the longest sugars: a chemical synthesis of heparin-related [4]<sub>n</sub>oligosaccharides from 16-mer to 40-mer

Hansen, Steen U.; Miller, Gavin J.; Cliff, Matthew J.; Jayson, Gordon C.; Gardiner, John M.

doi:10.1039/c5sc02091c

Cited by 82 publications

(50 citation statements)

References 52 publications

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“…22 These approaches are, however, mainly focused on the preparation of compounds composed of the same repeating unit and therefore are less suited to prepare HS oligosaccharides for SAR studies. We are developing a modular approach for HS oligosaccharide synthesis that uses a set of building blocks that resemble the differently sulfated disaccharides found in HS.…”

Section: Resultsmentioning

confidence: 99%

“…We are developing a modular approach for HS oligosaccharide synthesis that uses a set of building blocks that resemble the differently sulfated disaccharides found in HS. 22c,23 These compounds can easily be converted into glycosyl donors and acceptors for rapid oligosaccharide assembly. The disaccharide building blocks are modified by selectively removable levulinoyl esters (Lev) 24 at positions where eventually sulfates need to be installed (Scheme 1).…”

Section: Resultsmentioning

confidence: 99%

“…The targeted octasaccharide 1 was assembled from modular disaccharides 2, 3, 4, and 5, 22c which could easily be converted into glycosyl donors 6, 7, 8, and 9 using standard manipulations (Scheme 1). Thus, a triflic acid mediated glycosylation of 6 with 5-amino-1-pentanol protected with N -benzyloxycarbonate and N -benzyl groups gave spacer-modified 10 in a yield of 56% as a separable mixture of α/β glycosides ( α/β = 3/1).…”

Section: Resultsmentioning

confidence: 99%

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Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Zong¹,

Huang²,

Condac³

et al. 2016

J. Am. Chem. Soc.

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An integrated methodology is described to establish ligand requirements for heparan sulfate (HS) binding proteins based on a workflow in which HS octasaccharides are produced by partial enzymatic degradation of natural HS followed by size exclusion purification, affinity enrichment using an immobilized HS-binding protein of interest, putative structure determination of isolated compounds by a hydrophilic interaction chromatography–high-resolution mass spectrometry platform, and chemical synthesis of well-defined HS oligosaccharides for structure–activity relationship studies. The methodology was used to establish the ligand requirements of human Roundabout receptor 1 (Robo1), which is involved in a number of developmental processes. Mass spectrometric analysis of the starting octasaccharide mixture and the Robo1-bound fraction indicated that Robo1 has a preference for a specific set of structures. Further analysis was performed by sequential permethylation, desulfation, and pertrideuteroacetylation followed by online separation and structural analysis by MS/MS. Sequences of tetrasaccharides could be deduced from the data, and by combining the compositional and sequence data, a putative octasaccharide ligand could be proposed (GlA-GlcNS6S-IdoA-GlcNS-IdoA2S-GlcNS6S-IdoA-GlcNAc6S). A modular synthetic approach was employed to prepare the target compound, and binding studies by surface plasmon resonance (SPR) confirmed it to be a high affinity ligand for Robo1. Further studies with a number of tetrasaccharides confirmed that sulfate esters at C-6 are critical for binding, whereas such functionalities at C-2 substantially reduce binding. High affinity ligands were able to reverse a reduction in endothelial cell migration induced by Slit2-Robo1 signaling.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

See 1 more Smart Citation

Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Zong¹,

Huang²,

Condac³

et al. 2016

J. Am. Chem. Soc.

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“…7–9 In comparison, methodologies for the preparation of glycopeptides carrying homogenous glycosaminoglycan are under developed. Much synthetic work related to proteoglycans has been on the synthesis of glycosaminoglycan oligosaccharides 39–4445–68 and the tetrasaccharide linker. 69–79 Recently, we have begun to develop a strategy towards the proteoglycan family glycopeptides with syndecan-3 as the target.…”

Section: Introductionmentioning

confidence: 99%

Obstacles and solutions for chemical synthesis of syndecan-3 (53–62) glycopeptides with two heparan sulfate chains

Yang

Yoshida

Yang

et al. 2016

Carbohydrate Research

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Proteoglycans play critical roles in many biological events. Due to their structural complexities, strategies towards synthesis of this class of glycopeptides bearing well-defined glycan chains are urgently needed. In this work, we give the full account of the synthesis of syndecan-3 glycopeptide (53–62) containing two different heparan sulfate chains. For assembly of glycans, a convergent 3+2+3 approach was developed producing two different octasaccharide amino acid cassettes, which were utilized towards syndecan-3 glycopeptides. The glycopeptides presented many obstacles for post-glycosylation manipulation, peptide elongation, and deprotection. Following screening of multiple synthetic sequences, a successful strategy was finally established by constructing partially deprotected single glycan chain containing glycopeptides first, followed by coupling of the glycan-bearing fragments and cleavage of the acyl protecting groups.

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“…Although digest products of native HS can be used to investigate HS properties, these are necessarily heterogeneous. Chemicals ynthesis of HS oligosaccharides allows full control of the structureo fr esultingo ligosaccharides, for example, enabling variable defined lengths [9][10][11] andp rogrammables ulfation. [12] NMR has been employed in recent years for structural investigation of HS fragment-protein interactions, to probe HS oligosaccharide protein-bound conformation, [13] or identification of binding site amino acids.…”

Section: Introductionmentioning

confidence: 99%

Single‐Molecule Fluorescence Detection of a Synthetic Heparan Sulfate Disaccharide

et al. 2016

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The first single‐molecule fluorescence detection of a structurally‐defined synthetic carbohydrate is reported: a heparan sulfate (HS) disaccharide fragment labeled with Alexa488. Single molecules have been measured whilst freely diffusing in solution and controlled encapsulation in surface‐tethered lipid vesicles has allowed extended observations of carbohydrate molecules down to the single‐molecule level. The diverse and dynamic nature of HS–protein interactions means that new tools to investigate pure HS fragments at the molecular level would significantly enhance our understanding of HS. This work is a proof‐of‐principle demonstration of the feasibility of single‐molecule studies of synthetic carbohydrates which offers a new approach to the study of pure glycosaminoglycan (GAG) fragments.

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Making the longest sugars: a chemical synthesis of heparin-related [4]_noligosaccharides from 16-mer to 40-mer

Abstract: Synthesis of the longest heparin-related oligosaccharide backbones is enabled by efficient iterative [4]n-mer homologations via solution-phase synthesis. Pure-Shift HSQC NMR provides a dramatic improvement in anomeric signal resolution.

Cited by 82 publications

References 52 publications

Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Obstacles and solutions for chemical synthesis of syndecan-3 (53–62) glycopeptides with two heparan sulfate chains

Single‐Molecule Fluorescence Detection of a Synthetic Heparan Sulfate Disaccharide

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Making the longest sugars: a chemical synthesis of heparin-related [4]noligosaccharides from 16-mer to 40-mer

Abstract: Synthesis of the longest heparin-related oligosaccharide backbones is enabled by efficient iterative [4]n-mer homologations via solution-phase synthesis. Pure-Shift HSQC NMR provides a dramatic improvement in anomeric signal resolution.

Cited by 82 publications

References 52 publications

Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Integrated Approach to Identify Heparan Sulfate Ligand Requirements of Robo1

Obstacles and solutions for chemical synthesis of syndecan-3 (53–62) glycopeptides with two heparan sulfate chains

Single‐Molecule Fluorescence Detection of a Synthetic Heparan Sulfate Disaccharide

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Making the longest sugars: a chemical synthesis of heparin-related [4]_noligosaccharides from 16-mer to 40-mer