The First Synthesis of a Thioglycoside Analogue of the Immunostimulant KRN7000

Dere, Ravindra T.; Zhu, Xiangming

doi:10.1021/ol8019555

Cited by 68 publications

(40 citation statements)

References 54 publications

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“…6) showed no bioactivity (28). The synthesis of S-glycoside of 1 (α-S-GalCer, 13) with no detectable bioactivity in mice in vitro or vivo was also achieved (58,59). (34,35).…”

Section: D-2 Modification Of the Galactose-ceramide Linkagementioning

confidence: 97%

Fifteen Years since the Development of KRN7000 – Structure-Activity Relationship Studies on Novel Glycosphingolipids Which Stimulate Natural Killer T Cells

Tashiro¹,

Mori

2010

TIGG

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Invariant natural killer (NK) T cells bridge innate and acquired immunity and play an important role in both protective and regulatory responses. NKT cell responses are induced by recognition of a complex of glycolipid antigens with CD1d, an antigen presenting protein of the immune system, with its invariant T cell receptors. KRN7000, an α-galactosyl ceramide developed by KIRIN Brewery Co. in 1995, stimulates NKT cells strongly to induce the production of a large amount of cytokines, and is used as a standard reagent for a positive control of NKT cell studies. At the beginning, KRN7000 was developed as an anticancer drug candidate. However, it induces both helper T (Th)1-type cytokines, which induce immunostimulatory activity, and Th2-type ones, which induce immunosuppressive activities, in large quantities at the same time. Its therapeutical use, therefore, is limited. Fifteen years has passed since the discovery of KRN7000, and a number of analogues of KRN7000 have been developed worldwide to solve the above problem. Many researchers are also trying to understand how NKT cells recognize the structure of glycolipids and induce cytokines. In this minireview, we discuss the structure-activity relationship studies on novel glycolipids which stimulate NKT cells efficiently.

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“…6) showed no bioactivity (28). The synthesis of S-glycoside of 1 (α-S-GalCer, 13) with no detectable bioactivity in mice in vitro or vivo was also achieved (58,59). (34,35).…”

Section: D-2 Modification Of the Galactose-ceramide Linkagementioning

confidence: 97%

Fifteen Years since the Development of KRN7000 – Structure-Activity Relationship Studies on Novel Glycosphingolipids Which Stimulate Natural Killer T Cells

Tashiro¹,

Mori

2010

TIGG

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“…8 2S,3S,4R)-2-azido-3,4-dihydroxyoctadecyl)carbamoyl)-3,4,5-tris(benzyloxy)-6-((benzyloxy)methyl) , 3H), 3.48 (brs, 1H), 3.35 (s, 1H), 3.23 (brs, 1H), 3.00 (brs, 1H), 2.32 (s, 1H), 1.66 (s, 1H), 1.54-1.50 (m, 1H), 1.42 (brs, 2H), 1.32-1.25 (m, 23H) (2S,3S,4S,5S,6S)-N-((2S,3S,4R)-2-Hexacosanamido-3,4-dihydroxyoctadecyl)-3,4,5-trihydroxy-6-(hydroxymethyl)piperidine-2-carboxamide (3)…”

Section: Benzyl (2s3s4s5s6s)-2-(((2s)-2-azido-2-((4s)-22-dimethymentioning

confidence: 99%

“…[3,4] A large number of KRN7000 analogues and related compounds have been synthesized and their activity towards NKT cell-activation has been tested. [3][4][5][6][7][8][9][10] Modifications of KRN7000 are roughly based on three modifiable parts: sugar head moiety, ceramide part, and sugar-ceramide linkage. Sugar moiety modification studies suggested that: (1) α-glycosidic bond is essential for NKT cell-stimulation activity; (2) minor changes on sugar head can result in activity loss except that C-6 position can tolerate small substitutions.…”

Section: Introductionmentioning

confidence: 99%

Synthesis of Iminosugar‐Containing KRN7000 Analogues

Zhang

2017

Chin. J. Chem.

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Three new iminosugar-containing KRN7000 (also referred to as α-GalCer) analogues were designed and synthesized. In the design, the galactose moiety of KRN7000 was replaced by iminosugars and the iminosugar structures were connected with ceramide in different manners with a C-glycosidic bond instead of the O-glycosidic bond. To our knowledge, this is the first report in which iminosugars are incorporated in KRN7000 structure modifications. The synthetic compounds were evaluated for their ability to stimulate cytokine release. The results may benefit better understanding of structure-activity relationships and facilitate future design of more KRN7000 derivatives.

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“…The synthesis of S-glycoside analogues of natural bioactive O-glycosides has been of interest as potential glycomimetics [25][26][27]. S-Glycosides are apparently more stable in vivo than native O-glycosides and also there is the possibility that they are more immunogenic, which is relevant to vaccine development [28].…”

Section: Scheme 3 Synthesis Of 10mentioning

confidence: 99%

Synthesis of a-O- and a-S-Glycosphingolipids Related to Sphingomonous cell Wall Antigens Using Anomerisation

2013

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Analogues of glycolipids from Spingomonadacaece with O-and S-and SO 2 -linkages have been prepared using chelation induced anomerisation promoted by TiCl 4 . Included are examples of the anomerisation of intermediates with O-and S-glycosidic linkages as well as isomerisation of β-thioglycuronic acids (β-glycosyl thiols). The β-O-glucuronide and β-O-galacturonide precursors were efficiently prepared using benzoylated trichloroacetimidates. β-Glycosyl thiols were precursors to β-S-derivatives. Triazole containing mimics of the natural glycolipids were prepared using CuI promoted azide-alkyne cycloaddition reactions in THF. The glycolipid antigens are being evaluated currently for their effects on iNKT cells.

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The First Synthesis of a Thioglycoside Analogue of the Immunostimulant KRN7000

Abstract: The first total synthesis of a thioglycoside analogue of KRN7000, a potential immunostimulant, is described. Two key intermediates are alpha-galactosyl thiol 4 and phytosphingosine derivative 5, which were both prepared from D-galactose.

Cited by 68 publications

References 54 publications

Fifteen Years since the Development of KRN7000 – Structure-Activity Relationship Studies on Novel Glycosphingolipids Which Stimulate Natural Killer T Cells

Fifteen Years since the Development of KRN7000 – Structure-Activity Relationship Studies on Novel Glycosphingolipids Which Stimulate Natural Killer T Cells

Synthesis of Iminosugar‐Containing KRN7000 Analogues

Synthesis of a-O- and a-S-Glycosphingolipids Related to Sphingomonous cell Wall Antigens Using Anomerisation

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