Synthesis and biological evaluation of α-galactosylceramide (KRN7000) and isoglobotrihexosylceramide (iGb3)

Xia, Chengfeng; Yao, Qian; Schumann, Johann; Rossy, Emmanuel; Chen, Wenlan; Zhu, Lizhi; Zhang, Wenpeng; Libero, Gennaro De; Wang, Peng George

doi:10.1016/j.bmcl.2006.01.040

Cited by 79 publications

(54 citation statements)

References 15 publications

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“…After the disclosure of the structure 1 by Kirin Brewery, 4) many reports on the synthesis of 1 were published from 1995 to 2011, [25][26][27][28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44] including practical synthesis of it by Kirin group. 25) As shown in Fig.…”

Section: Synthesis Of Krn7000mentioning

confidence: 99%

“…Hence the synthesis of 1 includes two key steps: -selective (or -specific) galactosylation, and the construction of three continuous asymmetric centers of the phytosphingosine chain. To connect a galactose part in -orientation, researchers have used 1-OH free garactopyranose (D), 30,33,44) thiogalactoside (E), 28,30,36,37,41) galactosyl trichloroacetimidate (F), [27][28][29][32][33][34]36,39,43) phosphite (G), 33) phosphate (H), 42) acetate (I), 37) or halide (J) as the galactose donor. 4,25,26,29,31,35,38,40) Hague, 31) and trichloroacetimidate (L) with trimethylsilyl triflate (60%) reported by Kimura et al, 32) gave the highest -stereoselectivity (exclusivity).…”

Section: Synthesis Of Krn7000mentioning

confidence: 99%

“…Fortunately, we can purchase D-ribo-phytosphingosine [(2S,3S,4R)-2-amino-1,3,4-octadecanetriol, B] in large quantities at a reasonable price, because it can be manufactured practically by fermentation, 45) and some groups have employed it as starting material. 29,34,41) However, commercially available B has a C18-length linear alkyl chain, and it is difficult to introduce functional groups, such as a hydroxy group, a double bond, or an aromatic ring, at the proper positions. It is also difficult to shorten or elongate its chain length.…”

Section: Synthesis Of Krn7000mentioning

confidence: 99%

See 2 more Smart Citations

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Tashiro

2012

Bioscience, Biotechnology, and Biochemistry

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Section: Synthesis Of Krn7000mentioning

confidence: 99%

Section: Synthesis Of Krn7000mentioning

confidence: 99%

Section: Synthesis Of Krn7000mentioning

confidence: 99%

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Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Tashiro

2012

Bioscience, Biotechnology, and Biochemistry

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“…S1; refs. 15,17,18). The glycolipids were dissolved in dimethyl sulfoxide at 1 mg/mL, and the working amount of glycolipids was then dissolved in PBS buffer.…”

Section: Reagentsmentioning

confidence: 99%

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

Zhou

Zhang²,

Xia³

et al. 2011

Molecular Cancer Therapeutics

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Certain glycolipid antigens for natural killer T (NKT) cells can direct the overall cytokine balance of the immune response. However, the molecular mechanism of Th1-or Th2-biased cytokine secretion by NKT cells is still unknown. Previously, we synthesized isoglobotrihexosylceramide (iGb3) analogues by introducing a hydroxyl group at C4 on the ceramide portion of iGb3 to produce 4-HO-iGb3 or to further deoxylation on the terminal galactose to produce 4 000 -dh-iGb3. Both modified iGb3, especially 4 000 -dh-iGb3, stimulated more IFN-g production by hepatic NKT cells, and thus elicited preferential Th1 responses. Here, we found that 4 000 -dh-iGb3-loaded bone marrow-derived dendritic cells (DC) could significantly inhibit growth of subcutaneous melanoma and suppress lung metastasis in C57BL/6 mice compared with unmodified iGb3-loaded DCs. In investigating the mechanisms of this improved activity, we found that 4 000 -dh-iGb3 stimulation increased STAT1 signaling by NKT cells, whereas the phosphorylation of Th2 type cytokine-associated transcription factor STAT6 signaling was not affected. Analysis of the structures of iGb3 and 4 000 -dh-iGb3 revealed that 4 000 -dh-iGb3 provides greater stability and affinity between glycolipid and CD1d or NKT TCR complex than iGb3. Thus, 4 000 -dh-iGb3 can improve the antitumor effects of a DC-

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“…The case for iGb3 as a mammalian NKT cell agonist ligand is strong and has been verifi ed by several other studies (13)(14)(15)(16), including a report that demonstrated a role for this ligand in the activation of NKT cells in the periphery (15). However, whether this ligand is unique in its ability to mediate intrathymic NKT cell selection has yet to be defi nitively demonstrated.…”

Section: The Hunt For Selecting Ligandsmentioning

confidence: 99%

Chewing the fat on natural killer T cell development

Godfrey¹,

McConville²,

Pellicci³

2006

The Journal of Cell Biology

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Natural killer T cells (NKT cells) are selected in the thymus by self-glycolipid antigens presented by CD1d molecules. It is currently thought that one specifi c component of the lysosomal processing pathway, which leads to the production of isoglobotrihexosylceramide (iGb3), is essential for normal NKT cell development. New evidence now shows that NKT cell development can be disrupted by a diverse range of mutations that interfere with different elements of the lysosomal processing and degradation of glycolipids. This suggests that lysosomal storage diseases (LSDs) in general, rather than one specifi c defect, can disrupt CD1d antigen presentation, leading to impaired development of NKT cells. Chewing the fat on natural killer T cell developmentDale I. Godfrey, Malcolm J. McConville, and Daniel G. Pellicci NKT cells are a specialized lineage of T cells that recognize glycolipid antigens presented by the major histocompatibility complex class I-like molecule CD1d (1). Current evidence suggests that NKT cells branch away from the mainstream T cell lineage at the CD4 + CD8 + double positive (DP) stage of development in the thymus (2). NKT cells are derived from the small fraction of thymocytes that have randomly generated CD1d-reactive T cell receptors (typically comprising Vα14-Jα18 combined with either Vβ8.2, Vβ7, or Vβ2). When these cells encounter CD1d molecules expressed by other DP thymocytes (the cell type responsible for intrathymic NKT cell selection), they diff erentiate toward the NKT cell lineage. The newly selected NKT cells are clearly distinct from other T cell types. They adopt an activated/memory phenotype, express NK receptors, and gain the capacity to produce high levels of cytokines within minutes of T cell receptor ligation (1).Considering that the frequency of NKT cells in humans is highly variable between individuals and that low NKT cell numbers are associated with a variety of immunological defects in mice and humans (3), it is critical that we understand the factors that regulate their development.Gadola et al. (on p. 2293 in this issue [4]) show that mutations in several lysosomal proteins cause impaired NKT cell development. This study suggests that normal lipid traffi cking and processing in the lysosome is critical for CD1d loading and NKT cell development and invites a reexamination of earlier fi ndings suggesting that there is only one major selecting ligand for NKT cells (5). The hunt for selecting ligandsOne of the major questions in the NKT cell fi eld is the identity of the glycolipid ligands responsible for the positive sel ection of NKT cells. CD1d molecules most likely bind their ligands as they recirculate through the endosomal/ lysosomal pathway of the DP cells before returning to the cell membrane to present the ligands to developing NKT cells (6-8). The prototypic NKT cell antigen is α-galacytosylceramide (α-GalCer) (9, 10), which is recognized by most, if not all, NKT cells in mice and humans. α-GalCer, a glycosphin golipid derived from marine sponges, is a potent agonis...

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Synthesis and biological evaluation of α-galactosylceramide (KRN7000) and isoglobotrihexosylceramide (iGb3)

Cited by 79 publications

References 15 publications

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Structure-Activity Relationship Studies of Novel Glycosphingolipids That Stimulate Natural Killer T-Cells

Enhanced Antitumor Effects by Chemical Modified IGb3 Analogues

Chewing the fat on natural killer T cell development

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