The Conformational Behaviour of Non-Hydrolizable Lactose Analogues: The Thioglycoside, Carbaglycoside, and Carba-Iminoglycoside Cases

Montero, Emilio; Garcı́a-Herrero, Alicia; Asensio, Juan Luis; Hirai, Keisuke; Ogawa, Seiichiro; Santoyo‐González, Francisco; Cañada, F. Javier; Jiménez‐Barbero, Jesús

doi:10.1002/(sici)1099-0690(200005)2000:10<1945::aid-ejoc1945>3.0.co;2-g

Cited by 63 publications

(33 citation statements)

References 47 publications

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“…[8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H). [8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H).…”

Section: Resultsmentioning

confidence: 99%

“…[8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H). It has been reported that these conformations are preferred for the analogous thiodisaccharides, [8,23] and it is worth mentioning that they are stabilized by the favourable interactions of the sulfur lone-pair disposed anti to the C-1Ј-O-1Ј bond (the exoanomeric effect). [7,8,23] The NOESY spectrum of 4 showed interresidue NOE enhancements between 1Ј-H and 3-H, and between 1Ј-H and 4-H, which seems to confirm the respective syn φ/syn ψ and syn φ/anti ψ conformations around the thioglycosidic linkage.…”

Section: Resultsmentioning

confidence: 99%

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Synthesis of Thiodisaccharide Sulfoxides and Sulfones – Determination of the Configuration of the Sulfur Stereocentre

2013

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The oxidation of per‐O‐acetyl S‐(1→3)‐ and S‐(1→4)‐linked thiodisaccharides containing glucose, gulose and galactose residues with an excess of m‐chloroperbenzoic acid gave the corresponding sulfoxides or sulfones. Sulfones were formed when the oxidation reaction was left for longer times. The sulfoxides were obtained as diastereomeric mixtures due to the chirality of the sulfur atom. Both diastereoisomers of the S‐(1→3)‐linked thiodisaccharide sulfoxides were isolated by column chromatography, whereas the S‐(1→4)‐linked analogues could not be separated. The absolute configuration of the sulfur stereocentre of the sulfoxides was assigned using NMR spectroscopy, taking into account the preferred conformations of the molecules, and the shielding/deshielding of proton signals caused by the anisotropy of the S=O bond and related effects. Most of the thiodisaccharide sulfoxides were successfully O‐deacetylated with MeOH/Et3N/H2O, but the sulfones underwent elimination reactions under these conditions. Therefore, the oxidation was performed on unprotected thiodisaccharides, and the corresponding sulfones were obtained in very good yields.

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“…[8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H). [8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H).…”

Section: Resultsmentioning

confidence: 99%

“…[8,23] Due to the length and flexibility of the C-S bond, many conformations may be formed by rotation through the torsion angles φ (i.e., 1Ј-H-C-1Ј-S-C-4) and ψ (i.e., C-1Ј-S-C-4-4-H). It has been reported that these conformations are preferred for the analogous thiodisaccharides, [8,23] and it is worth mentioning that they are stabilized by the favourable interactions of the sulfur lone-pair disposed anti to the C-1Ј-O-1Ј bond (the exoanomeric effect). [7,8,23] The NOESY spectrum of 4 showed interresidue NOE enhancements between 1Ј-H and 3-H, and between 1Ј-H and 4-H, which seems to confirm the respective syn φ/syn ψ and syn φ/anti ψ conformations around the thioglycosidic linkage.…”

Section: Resultsmentioning

confidence: 99%

Synthesis of Thiodisaccharide Sulfoxides and Sulfones – Determination of the Configuration of the Sulfur Stereocentre

2013

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“…The precise understanding of the parameters governing those changes is therefore essential to the design of new and more efficient therapeutic molecules. More specifically, the replacement of the exocyclic anomeric oxygen atom by a carbon atom leads to C ‐glycosides5 while replacement of the endocyclic one produces carbasugars 6. In both cases, when the aglycone is another glycoside, this transformation leads to non‐hydrolysable disaccharide analogues: C ‐disaccharides and carbadisaccharides (Figure 1).…”

Section: Second‐order Interaction Energy (E2 Kcal Mol−1) Between Donmentioning

confidence: 99%

gem‐Difluorocarbadisaccharides: Restoring the exo‐Anomeric Effect

Unione

Sardinha

et al. 2014

Angew Chem Int Ed

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Molecular mimicry is an essential part of the development of drugs and molecular probes. In the chemical glycobiology field, although many glycomimetics have been developed in the past years, it has been considered that many failures in their use are related to the lack of the anomeric effects in these analogues. Additionally, the origin of the anomeric effects is still the subject of virulent scientific debates. Herein, by combining chemical synthesis, NMR methods, and theoretical calculations, we show that it is possible to restore the anomeric effect for an acetal when replacing one of the oxygen atoms by a CF2 group. This result provides key findings in chemical sciences. On the one hand, it strongly suggests the key relevance of the stereoelectronic component of the anomeric effect. On the other hand, the CF2 analogue adopts the natural glycoside conformation, which might provide new avenues for sugar-based drug design.

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“…S -Glycosides have been used as replacements for O -glycosides because of their similar conformational preferences about the anomeric bonds19 and because of the lower susceptibility of thioglycosides to enzymatic cleavage 20. Although a C-S bond is longer than a C-O bond, the C-S-C bond angle is significantly smaller than the C-O-C angle, which results in relatively small differences between the positions of the atoms along the glycosidic linkage.…”

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confidence: 99%

α-S-GalCer: Synthesis and evaluation for iNKT cell stimulation

Blauvelt¹,

Khalili²,

Jaung³

et al. 2008

Bioorganic & Medicinal Chemistry Letters

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The synthesis and evaluation for iNKT stimulation of α-S-galactosylceramide is reported. Prepared by alkylation of a galactosylthiol, this analog of the potent immunostimulatory agent, KRN7000, did not stimulate iNKT cells either in vitro or in vivo.Invariant Natural Killer T (iNKT) cells are potent regulatory T cells that have been shown to either initiate or shut down a wide range of immune responses. 1 A variety of bacteria, viruses and parasites have been demonstrated to trigger the anti-infective activity of iNKT cells, 2 and iNKT cells have also been implicated in anti-tumor responses. 3 In the absence of microbial or neoplastic triggers, it appears that iNKT cells may regulate the immune system in such a way as to prevent autoimmunity. 4 A little more than a decade ago it was revealed that glycolipids, particularly α-galactosylceramides (α-GalCers), could activate iNKT cells by a pathway involving their binding to a class of antigen presenting protein, CD1d. 5 This discovery has sparked intense efforts to understand the CD1d pathway of iNKT cell activation and to harness it for therapeutic purposes. 6A synthetic α-GalCer, KRN7000 (Figure 1), has been an invaluable tool for dissecting the function of CD1d activated iNKT cells. For example, the use of KRN7000 as a specific agonist for in vivo stimulation has provided evidence suggesting that NKT cell-mediated pathways may be used to inhibit hepatitis B virus replication 7 or protect against cancer, 5 diabetes, 8 malaria 9 and tuberculosis. 10 Not surprisingly, considerable effort has been spent on structure/ activity investigations. These studies have more recently been aided by crystal structures of ligand-bound mouse 11 -and human 12 -CD1d and even more recently by the report of a ternary structure of human iNKT T cell receptor (TCR)/CD1d/KRN7000. 13One key compound to emerge from SAR investigations is α-C-GalCer (Figure 1). 14 Part of the reason it has inspired so much interest is its superiority to KRN7000 in murine model cure ratios for malaria (1000/1 α-C-GalCer/KRN7000) and melanoma (100/1) 15 and for eradication of tumors in mice. 16 The strong activity of α-C-GalCer is not well understood. Both human and mouse CD1d/glycolipid binary structures show a hydrogen bond between CD1d and the anomeric oxygen of the bound α-GalCers (this hydrogen bond is not present in the ternary Correspondence to: Amy R. Howell. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. iNKT TCR/CD1d/KRN7000 complex). Consequently, it would be anticipated that the stability of the complex of α-C-GalCer, lacking an anomeric oxygen, wit...

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The Conformational Behaviour of Non-Hydrolizable Lactose Analogues: The Thioglycoside, Carbaglycoside, and Carba-Iminoglycoside Cases

Cited by 63 publications

References 47 publications

Synthesis of Thiodisaccharide Sulfoxides and Sulfones – Determination of the Configuration of the Sulfur Stereocentre

Synthesis of Thiodisaccharide Sulfoxides and Sulfones – Determination of the Configuration of the Sulfur Stereocentre

gem‐Difluorocarbadisaccharides: Restoring the exo‐Anomeric Effect

α-S-GalCer: Synthesis and evaluation for iNKT cell stimulation

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