Limits...
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.

Show MeSH
Reagents: (a) From 12: CBr4, PPh3, CH2Cl2, then 8, nBu4NBr, tetramethyl urea, 67% (α:β ratio: 1:1); (b) from 13: 8, SnCl4, AgIO4, THF, 41% (α:β ratio: 5:1).
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4374101&req=5

fig5: Reagents: (a) From 12: CBr4, PPh3, CH2Cl2, then 8, nBu4NBr, tetramethyl urea, 67% (α:β ratio: 1:1); (b) from 13: 8, SnCl4, AgIO4, THF, 41% (α:β ratio: 5:1).

Mentions: Although this synthetic approach allowed a completely stereoselective route to our target amine 11, a number of steps in the sequence suffered from poor yields, which hindered access to significant quantities of material. We therefore examined other glycosylation methods. Kobayashi has described a stereoselective α-glycosylation using a galactosyl bromide generated in situ from 2,3,4,6-tetra-O-benzyl galactose.23 Unfortunately, we found that glycosylation using the corresponding glucosyl bromide derived from 12 afforded significant amounts of the unwanted β-anomer (Scheme 2). The use of perbenzylated glucosyl fluoride 1324 also provided a mixture of α- and β-glycosides 14, which proved difficult to separate (Scheme 2).


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)

Reagents: (a) From 12: CBr4, PPh3, CH2Cl2, then 8, nBu4NBr, tetramethyl urea, 67% (α:β ratio: 1:1); (b) from 13: 8, SnCl4, AgIO4, THF, 41% (α:β ratio: 5:1).
© Copyright Policy
Related In: Results  -  Collection

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

fig5: Reagents: (a) From 12: CBr4, PPh3, CH2Cl2, then 8, nBu4NBr, tetramethyl urea, 67% (α:β ratio: 1:1); (b) from 13: 8, SnCl4, AgIO4, THF, 41% (α:β ratio: 5:1).
Mentions: Although this synthetic approach allowed a completely stereoselective route to our target amine 11, a number of steps in the sequence suffered from poor yields, which hindered access to significant quantities of material. We therefore examined other glycosylation methods. Kobayashi has described a stereoselective α-glycosylation using a galactosyl bromide generated in situ from 2,3,4,6-tetra-O-benzyl galactose.23 Unfortunately, we found that glycosylation using the corresponding glucosyl bromide derived from 12 afforded significant amounts of the unwanted β-anomer (Scheme 2). The use of perbenzylated glucosyl fluoride 1324 also provided a mixture of α- and β-glycosides 14, which proved difficult to separate (Scheme 2).

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