A new linker for solid-phase synthesis of heparan sulfate precursors by sequential assembly of monosaccharide building blocks

Czechura, Pawel; Guedes, Nerea; Kopitzki, Sebastian; Vázquez, Naiara; Martín‐Lomas, Manuel; Reichardt, Niels‐Christian

doi:10.1039/c0cc04686h

Cited by 39 publications

(39 citation statements)

References 31 publications

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“…4 Idohexopyranoses are important precursors in much needed new approaches to heparan sulphate synthesis. 5 Furthermore, methyl α- l -idopyranosiduronic acid (α- l -IdoA - 3 , Figure 1), a constituent in heparan and dermatan sulfates and the widely used antithrombic drug heparin, 6 was recently predicted 1 to undergo microsecond puckering that depends on substituents and epimerization and is crucial to bioactivity ( e.g ., anticoagulation). 7 …”

Section: Introductionmentioning

confidence: 99%

Dependence of Pyranose Ring Puckering on Anomeric Configuration: Methyl Idopyranosides

et al. 2012

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In the aldohexopyranose idose, the unique presence of three axial ring hydroxyl groups causes considerable conformational flexibility, rendering it challenging to study experimentally and an excellent model for rationalising the relationship between puckering and anomeric configuration. Puckering in methyl α- and β-l-idopyranosides was predicted from kinetically rigorous 10 μs simulations using GLYCAM11 and three explicit water models (TIP3P, TIP4P and TIP4P-EW). In each case, computed pyranose ring three-bond (vicinal) 1H-1H spin-couplings (3JH,H) trended with NMR measurements. These values, calculated puckering exchange rates and free energies were independent of the water model. The α- and β-anomers were 1C4 chairs for 85% and >99% of their respective trajectories and underwent 1C4→4C1 exchange at rates of 20 μs-1 and 1 μs-1. Computed α-anomer 1C4↔4C1 puckering rates depended on the exocyclic C6 substituent, comparing hydroxymethyl with carboxyl from previous work. The slower kinetics and restricted pseudorotational profile of the β-anomer were caused by water occupying a cavity bounded by the anomeric 1-O-methyl and the C6 hydroxymethyl groups. This finding rationalises the different methyl α- and β-l-idopyranoside 3JH,H values. Identifying a relationship between idopyranose anomeric configuration, μs-puckering and water structure facilitates engineering of biologically and commercially important derivatives and underpins deciphering presently elusive structure-function relationships in the glycome.

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Section: Introductionmentioning

confidence: 99%

Dependence of Pyranose Ring Puckering on Anomeric Configuration: Methyl Idopyranosides

et al. 2012

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“…This limitation might be addressed by using less hydrophobic substrates such as PEG-grafted PS resins, which have been used to assemble protected HS oligosaccharides. 17 To our knowledge, on-resin deprotection and sulfonation steps for such derivatives have not yet been reported, although we note a case in which a sulfate ester was installed on a synthetic tetrasaccharide immobilized on a polymeric PEG support. 18 …”

Section: Resultsmentioning

confidence: 88%

Solid-Phase Synthesis of 2-Aminoethyl Glucosamine Sulfoforms

Liu

Wei

2012

Journal of Carbohydrate Chemistry

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Mono- and disaccharides of sulfonated glucosamines (GlcN sulfoforms) conjugated to 2-aminoethyl linkers were generated by solid-phase synthesis. Orthogonally protected intermediates were tethered onto tritylated polystyrene resin beads, subjected to a modular sequence of deprotection and sulfonation steps, then cleaved from solid support without degradation of N- or O-sulfate esters using solvolytic conditions, and finally purified by reverse-phase HPLC to afford the title compounds.

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“…Disaccharide 2 was prepared as reported previously, exploiting our scalable iduronate thioglycoside acceptor capabilities for constructing such reagents5758, and is a reverse of the common IdoA-GlcN disaccharide repeat unit seen in several previous heparin-related syntheses101112131415161718192021222324252627282930313233343536. Disaccharide 2 was divergently elaborated into trichloroacetimidate donor 4 (see Supplementary Figs S5–S12) via free sugar disaccharide 3 (see Supplementary Figs S1–S4) and acceptor 5, with these two building blocks then efficiently coupled to afford tetrasaccharide 6 (Fig.…”

Section: Resultsmentioning

confidence: 99%

“…Although methods for the isolation of natural H/HS samples from biochemical degradation processes are well-established89, synthetic access to structurally defined H/HS mimetics has also received very significant attention101112131415161718192021222324252627282930313233343536. Synthetic access is essential to provide structurally defined H/HS oligosaccharide sequences to interrogate the chemical biology of H/HS-mediated processes, a better understanding of which also offers the potential to aid development of new disease treatments3738394041.…”

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confidence: 99%

Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies

et al. 2013

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Heparin-like oligosaccharides mediate numerous important biological interactions, of which many are implicated in various diseases. Synthetic improvements are central to the development of such oligosaccharides as therapeutics and, in addition, there are no methods to elucidate the pharmacokinetics of structurally defined heparin-like oligosaccharides. Here we report an efficient two-cycle [4+4+4] tetrasaccharide-iteration-based approach for rapid chemical synthesis of a structurally defined heparin-related dodecasaccharide, combined with the incorporation of a latent aldehyde tag, unmasked in the final step of chemical synthesis, providing a generic end group for labelling/conjugation. We exploit this latent aldehyde tag for 3H radiolabelling to provide the first example of this kind of agent for monitoring in vivo tissue distribution and in vivo stability of a biologically active, structurally defined heparin related dodecasaccharide. Such studies are critical for the development of related saccharide therapeutics, and the data here establish that a biologically active, synthetic, heparin-like dodecasaccharide provides good organ distribution, and serum lifetimes relevant to developing future oligosaccharide therapeutics.

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A new linker for solid-phase synthesis of heparan sulfate precursors by sequential assembly of monosaccharide building blocks

Abstract: A novel ester type linker which upon cleavage releases the glycans as carbamate protected aminoglycosides was successfully employed in the sequential assembly of L-idose and azido glucose monosaccharide building blocks to heparan sulfate precursors.

Cited by 39 publications

References 31 publications

Dependence of Pyranose Ring Puckering on Anomeric Configuration: Methyl Idopyranosides

Dependence of Pyranose Ring Puckering on Anomeric Configuration: Methyl Idopyranosides

Solid-Phase Synthesis of 2-Aminoethyl Glucosamine Sulfoforms

Tetrasaccharide iteration synthesis of a heparin-like dodecasaccharide and radiolabelling for in vivo tissue distribution studies

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