Total synthesis of sulfated Lex and Lea-type oligosaccharide selectin ligands

Nicolaou, K. C.; Bockovich, N. J.; Carcanague, Daniel R.

doi:10.1021/ja00072a049

Cited by 100 publications

(24 citation statements)

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“…Oligosaccharide Standards-Sulfated tri-, tetra-, and pentasaccharides of the Le a series were synthesized chemically: HSO 3 -3Gal␤1-3(Fuc␣1-4)GlcNAc and HSO 3 -3Gal␤1-3(Fuc␣1-4)GlcNAc␤1-3Gal (31) were gifts of Dr. K. C. Nicolaou (Scripps Research Institute, La Jolla, CA) and HSO 3 -3Gal␤1-3 (Fuc␣1-4)GlcNAc␤1-3Gal␤1-4Glc (32) was a gift of Dr. A. Lubineau (University Paris, Orsay, France). Man␣1-2Man and Fuc␣1-2Gal were from BioCarb through Russell Fine Chemicals (Chester, United Kingdom) and Glc␣1-2Glc was from Dextra Laboratories (Reading, United Kingdom).…”

Section: Methodsmentioning

confidence: 99%

Brain Contains HNK-1 Immunoreactive O-Glycans of the Sulfoglucuronyl Lactosamine Series that Terminate in 2-Linked or 2,6-Linked Hexose (Mannose)

Yuen

Chai

Loveless

et al. 1997

Journal of Biological Chemistry

118

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The monoclonal antibody HNK-1 originally raised to an antigenic marker of natural killer cells also binds to selected regions in nervous tissue. The antigen is a carbohydrate that has attracted much interest as its expression is developmentally regulated in nervous tissue, and it is found, and proposed to be a ligand, on several of the adhesive glycoproteins of the nervous system. It is also expressed on glycolipids and proteoglycans, and is the target of monoclonal auto-antibodies that give rise to a demyelinating disease. The epitope, as characterized on glycolipids isolated from the nervous system, is expressed on 3-sulfated glucuronic acid joined by ␤1-3-linkage to a neolacto backbone. Here we exploit the neoglycolipid technology, in conjunction with immunodetection and in situ liquid secondary ion mass spectrometry, to characterize HNK-1-positive oligosaccharide chains derived by reductive alkaline release from total brain glycopeptides. The immunoreactive oligosaccharides detected are tetra-to octasaccharides that are very minor components among a heterogeneous population, each representing less than 0.1% of the starting material. Their peripheral and backbone sequences resemble those of the HNK-1-positive glycolipids. An unexpected finding is that they terminate not with N-acetylgalactosaminitol but with hexitol (2-substituted and 2,6-disubstituted). In a tetrasaccharide investigated in the greatest detail, the hexitol is identified as 2-substituted mannitol.Monoclonal antibodies raised with the aim of identifying developmentally regulated antigens and differentiation antigens that have biological functions are in many cases directed to oligosaccharides of glycoproteins or glycolipids (1). Prominent among such antigens are those based on backbone sequences of the poly-N-acetyllactosamine type that are O-or N-glycosidically linked to proteins or to a glucose core of glycolipids (1, 2), several of which are now established ligands for carbohydrate-binding proteins of animals (3-6); and there is much interest in the biological events elicited by the carbohydrate-protein interactions. HNK-1 antigen, recognized by a hybridoma antibody, is a carbohydrate antigen first identified as a marker of the natural killer cell population among lymphocytes (7), and later found to be expressed on glycolipids (8 -10) as well as several glycoproteins (11) and proteoglycans (12) of the nervous system, with a changing distribution at different stages of development (13-15). HNK-1 antigen, as characterized biochemically on glycolipids, is expressed on 3-sulfated glucuronic acid joined by ␤1-3-linkage to a (poly)Nacetyllactosamine backbone (8 -10). This carbohydrate sequence has been implicated as a ligand for the leukocyteendothelium adhesion molecules, L-and P-selectins (16,17) and for a number of cell-interaction systems in nervous tissue (11, 18), notably as a ligand for the major glycoprotein of myelin, P o , in the peripheral nervous system (19), the extracellular matrix protein, laminin (20), and an adhesive protein, amph...

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Section: Methodsmentioning

confidence: 99%

Brain Contains HNK-1 Immunoreactive O-Glycans of the Sulfoglucuronyl Lactosamine Series that Terminate in 2-Linked or 2,6-Linked Hexose (Mannose)

Yuen

Chai

Loveless

et al. 1997

Journal of Biological Chemistry

118

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“…For example, PAPS has been synthesized both chemically and enzymatically in several syntheses. [173][174][175][176][177][178] Furthermore, chemical syntheses of various sulfated sialyl Lewis x (sLe x ) structures, [179] chemoenzymatic syntheses of 6'-sulfo-sLe x [180] and chondroitin sulfate E, [181] and syntheses of glycosulfopeptides by both chemical and enzymatic reactions [122,182] have been reported. However, examples of the use of STs in synthesis are rare.…”

Section: Synthetic Applicationsmentioning

confidence: 99%

Sulfotransferases: Structure, Mechanism, Biological Activity, Inhibition, and Synthetic Utility

et al. 2004

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The sulfonation (also known as sulfurylation) of biomolecules has long been known to take place in a variety of organisms, from prokaryotes to multicellular species, and new biological functions continue to be uncovered in connection with this important transformation. Early studies of sulfotransferases (STs), the enzymes that catalyze sulfonation, focused primarily on the cytosolic STs, which are involved in detoxification, hormone regulation, and drug metabolism. Although known to exist, the membrane-associated STs were not studied as extensively until more recently. Involved in the sulfonation of complex carbohydrates and proteins, they have emerged as central players in a number of molecular-recognition events and biochemical signaling pathways. STs have also been implicated in many pathophysiological processes. As a result, much interest in the complex roles of STs and in their targeting for therapeutic intervention has been generated. Progress in the elucidation of the structures and mechanisms of sulfotransferases, as well as their biological activity, inhibition, and synthetic utility, are discussed in this Review.

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“…Synthetic sulfo Le x derivative SE-3Galβ1-4(Fucα1-3)GlcNAcβ1-OMe 2 is recognized by all three selectins (Koenig et al, 1997). These findings stimulated interest in the chemical and enzymatic synthesis of SLe x 1 and its isomer SLe a , Neu5Acα2-3Galβ1-3(Fucα1-4)GlcNAcβ1-OMe (structure 3), their sulfated analogs and other modified structures related to these motifs (for example, Nicolaou et al, 1991Nicolaou et al, , 1993Tyrrel et al, 1991;Maaheimo et al, 1995;Bamford et al, 1996;Dupre et al, 1996;Marron et al, 1996;Sanders et al, 1996;Sprengard et al, 1996;Tsuboi et al, 1996;Woltering et al, 1996).…”

Section: Introductionmentioning

confidence: 99%

Inhibition of L- and P-selectin by a rationally synthesized novel core 2-like branched structure containing GalNAc-Lewisx and Neu5Ac 2-3Gal 1-3GalNAc sequences

Jain¹,

Piskorz

Huang

et al. 1998

Glycobiology

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The selectins interact in important normal and pathological situations with certain sialylated, fucosylated glycoconjugate ligands containing sialyl Lewis x (Neu5Acα2-3Galβ1-4(Fuc-α1-3)GlcNAc). Much effort has gone into the synthesis of sialylated and sulfated Lewis x analogs as competitive ligands for the selectins. Since the natural selectin ligands GlyCAM-1 and PSGL-1 carry sialyl Lewis x as part of a branched Core 2 O-linked structure, we recently synthesized Galβ1-4(Fuc-α1-3)GlcNAcβ1-6(SE-3Galβ1-3)GalNAc1αOMe and found it to be a moderately superior ligand for L and P-selectin (Koenig et al., Glycobiology 7, 79-93, 1997). Other studies have shown that sulfate esters can replace sialic acid in some selectin ligands (Yeun et al., Biochemistry, 31, 9126-9131, 1992; Imai et al., Nature, 361, 555, 1993). Based upon these observations, we hypothesized that Neu5Acα2-3Galβ1-3Gal-NAc might have the capability of interacting with L-and P-selectin. To examine this hypothesis, we synthesized Galβ1-4(Fucα1-3)GlcNAcβ1-6(Neu5Acα2-3Galβ1-3)-GalNAcα1-OB, which was found to be 2-to 3-fold better than sialyl Le x for P and L selectin, respectively. We also report the synthesis of an unusual structure GalNAcβ1-4(Fucα1-3)GlcNAcβ1-OMe (GalNAc-Lewis x -O-methyl glycoside), which also proved to be a better inhibitor of L-and P-selectin than sialyl Lewis x -OMe. Combining this with our knowledge of Core 2 branched structures, we have synthesized a molecule that is 5-to 6-fold better at inhibiting L-and P-selectin than sialyl Lewis x -OMe, By contrast to unbranched structures, substitution of a sulfate ester group for a sialic acid residue in such a molecule resulted in a considerable loss of inhibition ability. Thus, the combination of a sialic acid residue on the primary (β1-3) arm, and a modified Le x unit on the branched (β1-6) arm on an O-linked Core 2 structure generated a monovalent synthetic oliogosaccharide inhibitor superior to SLe x for both L-and P-selectin.

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Total synthesis of sulfated Lex and Lea-type oligosaccharide selectin ligands

Cited by 100 publications

References 0 publications

Brain Contains HNK-1 Immunoreactive O-Glycans of the Sulfoglucuronyl Lactosamine Series that Terminate in 2-Linked or 2,6-Linked Hexose (Mannose)

Brain Contains HNK-1 Immunoreactive O-Glycans of the Sulfoglucuronyl Lactosamine Series that Terminate in 2-Linked or 2,6-Linked Hexose (Mannose)

Sulfotransferases: Structure, Mechanism, Biological Activity, Inhibition, and Synthetic Utility

Inhibition of L- and P-selectin by a rationally synthesized novel core 2-like branched structure containing GalNAc-Lewisx and Neu5Ac 2-3Gal 1-3GalNAc sequences

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