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Synthesis and biological activity of alpha-glucosyl C24:0 and C20:2 ceramides.

Jervis PJ, Veerapen N, Bricard G, Cox LR, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

Bottom Line: Alpha-glucosyl ceramides 4 and 5 have been synthesised and evaluated for their ability to stimulate the activation and expansion of human iNKT cells.The key challenge in the synthesis of both target molecules was the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, glycosylation using per-TMS-protected glucosyl iodide 16 was completely alpha-selective and provided gram quantities of amine 11, from which alpha-glucosyl ceramides 4 and 5 were obtained by N-acylation. alpha-GlcCer 4, containing a C24 saturated acyl chain, stimulated a marked proliferation and expansion of human circulating iNKT cells in short-term cultures. alpha-GlcCer 5, which contains a C20 11,14-cis-diene acyl chain (C20:2), induced extremely similar levels of iNKT cell activation and expansion.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.

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α-Galactosyl ceramides 1 (C26:0), 2 (C24:0) and 3 (C20:2).
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fig1: α-Galactosyl ceramides 1 (C26:0), 2 (C24:0) and 3 (C20:2).

Mentions: CD1d is a non-polymorphic glycoprotein expressed on the surface of antigen-presenting cells (APCs). It is specifically associated with presenting lipid antigens that activate the distinctive class of T cells known as invariant Natural Killer T (iNKT) cells. iNKT cells display characteristics of both T cells and NK cells and play a crucial role in diverse immune responses and other pathologic conditions.1–4 When the synthetic glycolipid α-galactosyl ceramide (α-GalCer),5 also known as KRN7000 (1, Fig. 1), is bound to CD1d and presented to T cell receptors (TCRs) on the surface of iNKT cells, the latter are activated to release diverse cytokines, including both Th1 and Th2 cytokines.6–8 Similar results are obtained with the more readily obtained C24:0 analogue (2, Fig. 1).9,10 It is believed that the release of Th1 cytokines may contribute to antitumour and antimicrobial functions, whilst the secretion of Th2 cytokines may help alleviate autoimmune diseases11–13 such as multiple sclerosis14 and arthritis.15 The opposing effects induced by Th1 and Th2 cytokines have complicated efforts to develop KRN7000 as a therapeutic agent, since it induces high levels of both types of cytokine and therefore may induce mixed and unpredictable biological effects.16 Switching the C26:0 acyl chain of KRN7000 for a C20 11,14-cis-diene acyl chain modifies the outcome of iNKT cell activation and potently induces a Th2-biased cytokine response.9 This C20:2 analogue (3, Fig. 1) also exhibits less stringent requirements for loading on to CD1d.10


Synthesis and biological activity of alpha-glucosyl C24:0 and C20:2 ceramides.

Jervis PJ, Veerapen N, Bricard G, Cox LR, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

α-Galactosyl ceramides 1 (C26:0), 2 (C24:0) and 3 (C20:2).
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4374101&req=5

fig1: α-Galactosyl ceramides 1 (C26:0), 2 (C24:0) and 3 (C20:2).
Mentions: CD1d is a non-polymorphic glycoprotein expressed on the surface of antigen-presenting cells (APCs). It is specifically associated with presenting lipid antigens that activate the distinctive class of T cells known as invariant Natural Killer T (iNKT) cells. iNKT cells display characteristics of both T cells and NK cells and play a crucial role in diverse immune responses and other pathologic conditions.1–4 When the synthetic glycolipid α-galactosyl ceramide (α-GalCer),5 also known as KRN7000 (1, Fig. 1), is bound to CD1d and presented to T cell receptors (TCRs) on the surface of iNKT cells, the latter are activated to release diverse cytokines, including both Th1 and Th2 cytokines.6–8 Similar results are obtained with the more readily obtained C24:0 analogue (2, Fig. 1).9,10 It is believed that the release of Th1 cytokines may contribute to antitumour and antimicrobial functions, whilst the secretion of Th2 cytokines may help alleviate autoimmune diseases11–13 such as multiple sclerosis14 and arthritis.15 The opposing effects induced by Th1 and Th2 cytokines have complicated efforts to develop KRN7000 as a therapeutic agent, since it induces high levels of both types of cytokine and therefore may induce mixed and unpredictable biological effects.16 Switching the C26:0 acyl chain of KRN7000 for a C20 11,14-cis-diene acyl chain modifies the outcome of iNKT cell activation and potently induces a Th2-biased cytokine response.9 This C20:2 analogue (3, Fig. 1) also exhibits less stringent requirements for loading on to CD1d.10

Bottom Line: Alpha-glucosyl ceramides 4 and 5 have been synthesised and evaluated for their ability to stimulate the activation and expansion of human iNKT cells.The key challenge in the synthesis of both target molecules was the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, glycosylation using per-TMS-protected glucosyl iodide 16 was completely alpha-selective and provided gram quantities of amine 11, from which alpha-glucosyl ceramides 4 and 5 were obtained by N-acylation. alpha-GlcCer 4, containing a C24 saturated acyl chain, stimulated a marked proliferation and expansion of human circulating iNKT cells in short-term cultures. alpha-GlcCer 5, which contains a C20 11,14-cis-diene acyl chain (C20:2), induced extremely similar levels of iNKT cell activation and expansion.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham, UK.

Show MeSH