Rapid Assembly of Oligosaccharides: A Highly Convergent Strategy for the Assembly of a Glycosylated Amino Acid Derived from PSGL-1

Abstract

P-selectin and P-selectin glycoprotein ligand 1 (PSGL-1) are vascular adhesion molecules that play an important role in the recruitment of leukocytes to inflamed tissue by establishing leukocyteendothelial and leukocyte-platelet interaction. P-selectin binds to the amino-terminus of PSGL-1 through recognition of a sialyl Lewis x (SLe x ) moiety linked to a properly positioned core-2 O-glycan and three tyrosine sulfate residues. We have developed a highly convergent synthesis of the PSGL-1 oligosaccharide linked to threonine based on the use of trichoroacetimidate donors and thioglycosyl acceptors that give products that can immediately be employed in a subsequent glycosylation step without the need for protecting group manipulations. Furthermore, by employing one-pot multi-step glycosylation sequences the number of purification steps could be minimized. The process of oligosaccharide assembly was further streamlined by combining protecting group manipulations and glycosylations as one-pot multi-step synthetic procedure. The resulting PSGL-1 oligosaccharide is properly protected for glycopeptide assembly. It is to be expected that the strategic principles employed for the synthesis of the target compound can be applied for the preparation of other complex oligosaccharides of biological and medical importance.

Targeting P-selectin glycoprotein ligand-1/P-selectin interactions as a novel therapy for metabolic syndrome

“…To date, the design of most existing P-selectin inhibitors has focused on mimicking the C2 O-glycan bearing sLe x moiety and in so doing, these approaches have been largely unsuccessful in accounting for the contribution of critical clustered tyrosine sulfates [119, 124, 130, 131, 138, 139]. Further synthetic challenges have included suboptimal selectivity in glycosylation [140], incompatible protecting groups for the synthesis of oligosaccharides [141], and the acid lability of tyrosine sulfates [142, 143], all of which have contributed to low yield of PSGL-1 GSP mimetics.…”

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

“…The TBDPS silyl ether groups in 50 were removed by HF/pyridine to expose the three primary hydroxyls, which were oxidized to carboxylic acids 92 and subsequently converted to methyl esters. The two azide groups were transformed to N -acetyl moieties through a one pot reduction/acetylation procedure 104 to afford octasaccharide 4 .…”

Characterization of the Viral O -Glycopeptidome: a Novel Tool of Relevance for Vaccine Design and Serodiagnosis

“…This is necessary not only to confirm the structural identity of the reactive glycoepitopes identified by the enzymatic screening method but also to analyze the relevance of each glycan's individual structural elements. Synthesis of large O-linked glycans, such as hexasaccharide selectin ligands, has been demonstrated via both chemical and enzymatic synthesis (24,40), but usually they require extensive purification strategies for each target structure. Our concept allows for direct on-slide enrichment of large libraries of synthetic products derived from the SPPS blocks and offers a comprehensive tool to rapidly study complete sets of sequences from target proteins without tedious purification protocols.…”