Synthesis of LacNAcLex‐ and DimLex‐BSA Conjugates and Binding to Anti‐Polymeric Lex mAbs

Nejatie, Ali; Jegatheeswaran, Sinthuja; Auzanneau, France‐Isabelle

doi:10.1002/ejoc.201901142

Cited by 4 publications

(4 citation statements)

References 27 publications

(34 reference statements)

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“…In turn, the five azidononyl oligosaccharide glycosides were submitted to one-step global deprotection in dissolving metal conditions to yield the final deprotected tri- to pentasaccharides aminononyl glycosides 3 , 4 , 6 , and 10 . As we have previously observed, the deprotection of the azidononyl pentasaccharide 56 also gave a non-negligible amount (16%) of the nonyl pentasaccharide 9 . The nonyl glycosides 5 and 7 were obtained, following full deprotection/reduction of protected chlorononyl analogues under dissolving metal conditions.…”

Section: Discussionsupporting

confidence: 79%

“…The structure of this pentasaccharide was confirmed in 1 H NMR, which showed a triplet at 0.86 ppm that correlated in the HSQC with a methyl group carbon at 16.3 ppm. While the reduction of a chloroalkyl glycoside in dissolving metal conditions is expected to lead to the corresponding alkyl glycoside, 40 this is the second instance 38 during which we observe the loss of an azido group from an azidoalkyl glycoside and the formation of the corresponding alkyl glycoside in non-negligible amount while reducing an azidoalkyl glycoside oligosaccharide. Furthermore, we observed that nonyl glycoside tetrasaccharide 9 had reduced solubility in water.…”

Section: ■ Results and Discussionmentioning

confidence: 75%

“…Trisaccharide 52 and crude tetrasaccharide 54 were then submitted to one-step global deprotection under dissolving metal conditions . Our group has routinely used dissolving metal conditions to globally deprotect oligosaccharide fragments with fair to good results. ,, Dissolving metal conditions are able to cleave esters, benzyls, and benzylidene acetals while also reducing a chloroalkyl or azidoalkyl aglycone to an alkyl or aminoalkyl aglycone, respectively. Thus, trisaccharide 52 and the crude tetrasaccharide 54 were treated with sodium in liquid ammonia at −78 °C in THF.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Dimeric Lewis A and Lewis B–Lewis A Tumor-Associated Carbohydrate Antigen Oligosaccharide Fragments

2023

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Despite the interesting potential of tumor-associated carbohydrate antigens (TACAs) dimLe a and Le b Le a to develop anticancer immunotherapies, little research has been conducted on these antigens. In our quest to discover fragments of these TACAs that could be targeted for the development of anticancer therapeutics, we report the synthesis of eight tri-to pentasaccharide fragments of these oligosaccharides. Unforeseen synthetic challenges are reported such as the incompatibility of a bromoalkyl glycoside in the reduction conditions needed to reduce a trichloroacetamide, the mismatched reactivities in a 2 + 1 synthetic strategy, and the surprising greater reactivity of a C-4 GlcNAc hydroxyl group versus that of the galactosyl OH-3 in the selective glycosylation of a trisaccharide diol. The desired final compounds were eventually obtained following a stepwise approach as nonyl or 9-aminononyl glycosides after one-step deprotection reactions in dissolving metal conditions. The 9-aminononyl glycosides will be conjugated to carrier proteins and the nonyl pentasaccharide glycoside will be used as a soluble inhibitor in binding experiments. In contrast, the nonyl tetrasaccharide glycosides are poorly soluble in water and their use in biochemical experiments will be limited.

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Section: Discussionsupporting

confidence: 79%

Section: ■ Results and Discussionmentioning

confidence: 75%

Section: Resultsmentioning

confidence: 99%

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Synthesis of Dimeric Lewis A and Lewis B–Lewis A Tumor-Associated Carbohydrate Antigen Oligosaccharide Fragments

2023

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“…We have previously reported the chemical synthesis of the DimLe x propyl hexasaccharide 6 as well as that of the Le x methyl glycoside 7 [ 38 , 43 ]. In addition, we have also described the synthesis of tri-, tetra-, and pentasaccharide fragments of DimLe x 8 , 10 – 14 [ 44 , 45 , 46 , 47 ] shown in Figure 3 . Tetrasaccharide fragment 9 (Lex[1,3]Gal, Figure 3 ) was a generous gift of Samain and co. [ 48 ].…”

Section: Resultsmentioning

confidence: 99%

Recognition of Dimeric Lewis X by Anti-Dimeric Lex Antibody SH2

et al. 2020

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The carbohydrate antigen dimeric Lewis X (DimLex), which accumulates in colonic and liver adenocarcinomas, is a valuable target to develop anti-cancer therapeutics. Using the native DimLex antigen as a vaccine would elicit an autoimmune response against the Lex antigen found on normal, healthy cells. Thus, we aim to study the immunogenic potential of DimLex and search internal epitopes displayed by DimLex that remain to be recognized by anti-DimLex monoclonal antibodies (mAbs) but no longer possess epitopes recognized by anti-Lex mAbs. In this context, we attempted to map the epitope recognized by anti-DimLex mAb SH2 by titrations and competitive inhibition experiments using oligosaccharide fragments of DimLex as well as Lex analogues. We compare our results with that reported for anti-Lex mAb SH1 and anti-polymeric Lex mAbs 1G5F6 and 291-2G3-A. While SH1 recognizes an epitope localized to the non-reducing end Lex trisaccharide, SH2, 1G5F6, and 291-2G3-A have greater affinity for DimLex conjugates than for Lex conjugates. We show, however, that the Lex trisaccharide is still an important recognition element for SH2, which (like 1G5F6 and 291-2G3-A) makes contacts with all three sugar units of Lex. In contrast to mAb SH1, anti-polymeric Lex mAbs make contact with the GlcNAc acetamido group, suggesting that epitopes extend further from the non-reducing end Lex. Results with SH2 show that this epitope is only recognized when DimLex is presented by glycoconjugates. We have reported that DimLex adopts two conformations around the β-d-GlcNAc-(1→3)-d-Gal bond connecting the Lex trisaccharides. We propose that only one of these conformations is recognized by SH2 and that this conformation is favored when the hexasaccharide is presented as part of a glycoconjugate such as DimLex-bovine serum albumin (DimLex-BSA). Proper presentation of the oligosaccharide candidate via conjugation to a protein or lipid is essential for the design of an anti-cancer vaccine or immunotherapeutic based on DimLex.

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Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2019–2020

Harvey

2023

Mass Spectrometry Reviews

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This review is the tenth update of the original article published in 1999 on the application of matrix‐assisted laser desorption/ionization (MALDI) mass spectrometry to the analysis of carbohydrates and glycoconjugates and brings coverage of the literature to the end of 2020. Also included are papers that describe methods appropriate to analysis by MALDI, such as sample preparation techniques, even though the ionization method is not MALDI. The review is basically divided into three sections: (1) general aspects such as theory of the MALDI process, matrices, derivatization, MALDI imaging, fragmentation, quantification and the use of arrays. (2) Applications to various structural types such as oligo‐ and polysaccharides, glycoproteins, glycolipids, glycosides and biopharmaceuticals, and (3) other areas such as medicine, industrial processes and glycan synthesis where MALDI is extensively used. Much of the material relating to applications is presented in tabular form. The reported work shows increasing use of incorporation of new techniques such as ion mobility and the enormous impact that MALDI imaging is having. MALDI, although invented nearly 40 years ago is still an ideal technique for carbohydrate analysis and advancements in the technique and range of applications show little sign of diminishing.

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Synthesis of LacNAcLe^x‐ and DimLe^x‐BSA Conjugates and Binding to Anti‐Polymeric Le^x mAbs

Cited by 4 publications

References 27 publications

Synthesis of Dimeric Lewis A and Lewis B–Lewis A Tumor-Associated Carbohydrate Antigen Oligosaccharide Fragments

Synthesis of Dimeric Lewis A and Lewis B–Lewis A Tumor-Associated Carbohydrate Antigen Oligosaccharide Fragments

Recognition of Dimeric Lewis X by Anti-Dimeric Lex Antibody SH2

Analysis of carbohydrates and glycoconjugates by matrix‐assisted laser desorption/ionization mass spectrometry: An update for 2019–2020

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