A Broadly Applicable Method for the Efficient Synthesis of α-<i>O</i>-Linked Glycopeptides and Clustered Sialic Acid Residues

Schwarz, Jacob B.; Kuduk, Scott D.; Chen, Xiaotao; Sameš, Dalibor; Glunz, Peter W.; Danishefsky, Samuel J.

doi:10.1021/ja9833265

Cited by 128 publications

(64 citation statements)

References 36 publications

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“…Regarding the sugar or aliphatic glycosyl acceptors, the general rule normally states that glycosylation of more reactive primary hydroxyl provides poorer stereoselectivity in comparison to that when the secondary hydroxyls are involved [111]. The same principles are applicable for the synthesis of glycopeptides; thus, the glycosylation of the secondary hydroxyl of threonine typically gives higher a-stereoselectivity than when primary hydroxyl group of serine is glycosylated with 2-azido-2-deoxy-galactosyl bromide or trichloroacetimidates [112,113]. Occasionally, primary hydroxyls provide somewhat higher 1,2-cis stereoselectivity in comparison to that of the secondary hydroxyl groups.…”

Section: Position Of the Hydroxylmentioning

confidence: 99%

General Aspects of the Glycosidic Bond Formation

Demchenko

2008

Handbook of Chemical Glycosylation

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Section: Position Of the Hydroxylmentioning

confidence: 99%

General Aspects of the Glycosidic Bond Formation

Demchenko

2008

Handbook of Chemical Glycosylation

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“…Structures 113 [94] and 114 [95] containing the 2,6-STF [96] and STn groups, [97] respectively, have been synthesized (Scheme 24). Conjugation and immunological evaluation of these constructs is currently well under way.…”

Section: Synthesis Of Clustered Tf Antigenmentioning

confidence: 99%

From the Laboratory to the Clinic: A Retrospective on Fully Synthetic Carbohydrate-Based Anticancer Vaccines

Danishefsky

Allen

2000

Angew. Chem. Int. Ed.

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499

335

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This review provides an account of our explorations into oligosaccharide and glycoconjugate construction for the creation and evaluation of vaccines based on carbohydrate-centered tumor antigens. Our starting point was the known tendency of transformed cells to express selective carbohydrate motifs in the form of glycoproteins or glycolipids. Anticancer vaccines derived from carbohydrate-based antigens could be effective targets for immune recognition and attack. Obtaining significant quantities of such structures from natural sources is, however, extremely difficult. With the total synthesis of tumor-associated carbohydrate antigens accomplished, we began to evaluate at the clinical level whether the human immune system can respond to such fully synthetic antigens in a focused and useful way. Toward this goal, we have merged the resources of chemistry and immunology in an attack on the problem. The synthesis and immunoconjugation of various tumor-associated carbohydrate antigens and the results of such constructs in mice vaccinations will be described. For fashioning an effective vaccine, conjugation to a suitable immunogenic carrier was necessary and conjugates of KLH (keyhole limpet cyanin) have consistently demonstrated the relevant immunogenicity. Preclinical and clinical studies with synthetic conjugate carbohydrate vaccines show induction of IgM- and IgG-antibody responses. Another approach to anticancer vaccines involves the use of clustered glycopeptides as targets for immune attack. Initial attention has been directed to mucin related O-linked glycopeptides. Synthetic trimeric clusters of glycoepitopes derived from the Tn-, TF- and Lewis(y)-antigens, appropriately bioconjugated, have been demonstrated to be immunogenic. The hope is that patients immunized in an adjuvant manner with synthetic carbohydrate vaccines would produce antibodies reactive with cancer cells and that the production of such antibodies would mitigate against tumor spread, thereby enabling a more favorable survival and "quality of life" prognosis.

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“…[108] In the reported syntheses of the building blocks containing the T antigen (core 1), the sialyl-T N antigen, the sialyl-T antigen, the bissialyl-T antigen and a basic substructure of a Lewis Y blood group determinant, the broad applicability of the ªcassette approachº was demonstrated. [109] As a common precursor, the 2-azidogalactosylthreonine derivative 37 was prepared by using either the fluoride or the trichloroacetimidate of the 6-silyl-protected acetonide of 2-azidogalactose 36 (Scheme 10). [110] Removal of the isopropylidene and the triisopropylsilyl ether groups and subsequent TBSprotection of the primary hydroxy group yielded the 3-acceptor 38.…”

Section: A-galnac-thr/sermentioning

confidence: 99%

Glycopeptide Synthesis and the Effects of Glycosylation on Protein Structure and Activity

Seitz

2000

ChemBioChem

196

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Despite the omnipresence of protein glycosylation in nature, little is known about how the attachment of carbohydrates affects peptide and protein activity. One reason is the lack of a straightforward method to access biologically relevant glycopeptides and glycoproteins. The isolation of homogeneous glycopeptides from natural sources is complicated by the heterogeneity of naturally occuring glycoproteins. It is chemical and chemoenzymatic synthesis that is meeting the challenge to solve this availability problem, thus playing a key role for the advancement of glycobiology. The current art of glycopeptide synthesis, albeit far from being routine, has reached a level of maturity that allows for the access to homogeneous and pure material for biological and medicinal research. Even the ambitious goal of the total synthesis of an entire glycoprotein is within reach. It is demonstrated that with the help of synthetic glycopeptides the effects of glycosylation on protein structure and function can be studied in molecular detail. For example, in immunology, synthetic (tumour-specific) glycopeptides can be used as immunogens to elicit a tumour-cell-specific immune response. Again, synthetic glycopeptides are an invaluable tool to determine the fine specificity of the immune response that can be mediated by both carbohydrate-specific B and T cells. Furthermore, selected examples for the use of synthetic glycopeptides as ligands of carbohydrate-binding proteins and as enzyme substrates or inhibitors are presented.

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A Broadly Applicable Method for the Efficient Synthesis of α-O-Linked Glycopeptides and Clustered Sialic Acid Residues

Abstract: The total syntheses of complex sialylated cell-surface antigens have been accomplished. The target systems include 2,3-STF, STn, 2,6-STF, and glycophorin antigens. In addition, an α-O-linked serine glycoside of an entire Lewis blood group (Y) antigen has been assembled.

Cited by 128 publications

References 36 publications

General Aspects of the Glycosidic Bond Formation

General Aspects of the Glycosidic Bond Formation

From the Laboratory to the Clinic: A Retrospective on Fully Synthetic Carbohydrate-Based Anticancer Vaccines

Glycopeptide Synthesis and the Effects of Glycosylation on Protein Structure and Activity

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