Convergent Synthesis of Sialyl Lewis^X-O-Core-1 Threonine

Abstract

Selectins are a class of cell adhesion molecules that play a critical role during the initial steps of inflammation. The N-terminal domain of P-selectin glycoprotein ligand-1 (PSGL-1) binds to all selectins, but with the highest affinity to P-selectin. Recent evidence suggests that the blockade of P-selectin/PSGL-1 interactions provides a viable therapeutic option for the treatment of many inflammatory diseases. Herein, we report the total synthesis of threonine bearing sialyl Lewis (sLe) linked to a Core-1- O-hexasaccharide 1, as a key glycan of the N-terminal domain of PSGL-1. A convergent synthesis using α-selective sialylation and a regioselective [4+2] glycosylation are the key features of this synthesis.

Automated Chemical Oligosaccharide Synthesis: Novel Approach to Traditional Challenges

“…The block synthesis is particularly useful for the purpose of the introduction of a "difficult" linkage at an earlier stage of the saccharide assembly. 359 Convergent block synthesis also streamlines the formation of oligosaccharide sequences containing two or more repeat units.…”

“…Additional protection/deprotection steps may still be required but the overall assembly is faster due to the use of oligomeric building blocks. The block synthesis is particularly useful for the purpose of the introduction of a “difficult” linkage at an earlier stage of the saccharide assembly . Convergent block synthesis also streamlines the formation of oligosaccharide sequences containing two or more repeat units.…”

Insights into Selectin Inhibitor Design from Endogenous Isomeric Ligands of SLea and SLex

“…37,38 Thus, many efforts have been devoted to the chemical synthetic approach 39,40 and led to synthetic glycomimetic selectin antagonists, such as Rivipansel (GMI-1070). However, compared to designing moieties with sulfate groups in inhibitors to mimic the sulfated amino acids in glycopeptides, the structural complexity underlying the stereospecific glycosidic linkages among monosaccharides requires more sophisticated strategies for placements of protecting groups and deprotecting processes, 39 which extensively complicate the chemical synthetic approaches and reduce the yield of the final product. Therefore, replacing nonbindingcritical residues with synthetic accessible ones has great potential in simplifying the synthetic process for selectin inhibitors.…”

“…The chemoenzymatic approach has been successfully employed in the synthesis of sLe x , but it has been limited by the cost, scalability, and variability. , Thus, many efforts have been devoted to the chemical synthetic approach , and led to synthetic glycomimetic selectin antagonists, such as Rivipansel (GMI-1070). However, compared to designing moieties with sulfate groups in inhibitors to mimic the sulfated amino acids in glycopeptides, the structural complexity underlying the stereospecific glycosidic linkages among monosaccharides requires more sophisticated strategies for placements of protecting groups and deprotecting processes, which extensively complicate the chemical synthetic approaches and reduce the yield of the final product. Therefore, replacing nonbinding-critical residues with synthetic accessible ones has great potential in simplifying the synthetic process for selectin inhibitors .…”

Diversity-Oriented Chemoenzymatic Synthesis of Sulfated and Nonsulfated Core 2 O-GalNAc Glycans

“…There was no significant improvement observed by optimizing reaction conditions such as different glycosyl donors and temperatures (Table S1). 34 To circumvent this limitation, we developed a facile three-step procedure in which acetyl (Ac) was introduced into C4-OH to afford only free C-6 hydroxyl acceptor 43 in an overall yield of 86%. Then a glycosylation of 43 with thioglycoside donor 40, using NIS/ AgOTf as the promoter system, afforded trisaccharide 44 in a yield of 85%.…”