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Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000.

Veerapen N, Reddington F, Bricard G, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

Bottom Line: Activation of iNKT cells is known to lead to the production of cytokines that can help alleviate or exacerbate these conditions. alpha-Galactosyl ceramide (alpha-GalCer) is a known agonist of iNKT cells and it is believed that its fucosyl counterpart might have similar immunogenic properties.The key challenge in the synthesis of the target molecules involved the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, the per-TMS-protected glycosyl iodide donor was completely alpha-selective, and could be scaled up to provide gram quantities of the azide precursor 11, from which a range of N-acylated alpha-L-fucosyl ceramides were readily obtained and evaluated for ex vivo expansion of human iNKT cells.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

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(a) TBAI, DIPEA, CH2Cl2, rt; (b) Dowex 50WX8-200, MeOH, rt, 62% over two steps; (c) NaOMe/MeOH, quantitative; (d) H2, Pd, MeOH, 80%; (e) C25H51COCl or C23H47COC1, THF, NaOAc, 78–80%.
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fig4: (a) TBAI, DIPEA, CH2Cl2, rt; (b) Dowex 50WX8-200, MeOH, rt, 62% over two steps; (c) NaOMe/MeOH, quantitative; (d) H2, Pd, MeOH, 80%; (e) C25H51COCl or C23H47COC1, THF, NaOAc, 78–80%.

Mentions: The per-O-trimethylsilyl-α-l-fucosylpyranosyl iodide 10 was generated by the reaction of the per-O-tetramethylsilyl-α-l-fucose with one equivalent of iodotrimethylsilane35 and then added to the phytosphingosine acceptor 7 which was premixed with diisopropylethylamine (DIPEA) and TBAI (Scheme 3). After 2 days at room temperature, the solvent was evaporated and the TMS protecting groups were removed by treatment with an acidic resin in MeOH. Compound 11 was obtained as the α-anomer exclusively in an overall yield of 62%. The formation of the desired α-linkage was confirmed by the H-1 and C-1 signals in 1H and 13C NMR. Methanolysis, followed by hydrogenation of the azide then afforded compound 9.


Synthesis and biological activity of alpha-L-fucosyl ceramides, analogues of the potent agonist, alpha-D-galactosyl ceramide KRN7000.

Veerapen N, Reddington F, Bricard G, Porcelli SA, Besra GS - Bioorg. Med. Chem. Lett. (2010)

(a) TBAI, DIPEA, CH2Cl2, rt; (b) Dowex 50WX8-200, MeOH, rt, 62% over two steps; (c) NaOMe/MeOH, quantitative; (d) H2, Pd, MeOH, 80%; (e) C25H51COCl or C23H47COC1, THF, NaOAc, 78–80%.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC2957807&req=5

fig4: (a) TBAI, DIPEA, CH2Cl2, rt; (b) Dowex 50WX8-200, MeOH, rt, 62% over two steps; (c) NaOMe/MeOH, quantitative; (d) H2, Pd, MeOH, 80%; (e) C25H51COCl or C23H47COC1, THF, NaOAc, 78–80%.
Mentions: The per-O-trimethylsilyl-α-l-fucosylpyranosyl iodide 10 was generated by the reaction of the per-O-tetramethylsilyl-α-l-fucose with one equivalent of iodotrimethylsilane35 and then added to the phytosphingosine acceptor 7 which was premixed with diisopropylethylamine (DIPEA) and TBAI (Scheme 3). After 2 days at room temperature, the solvent was evaporated and the TMS protecting groups were removed by treatment with an acidic resin in MeOH. Compound 11 was obtained as the α-anomer exclusively in an overall yield of 62%. The formation of the desired α-linkage was confirmed by the H-1 and C-1 signals in 1H and 13C NMR. Methanolysis, followed by hydrogenation of the azide then afforded compound 9.

Bottom Line: Activation of iNKT cells is known to lead to the production of cytokines that can help alleviate or exacerbate these conditions. alpha-Galactosyl ceramide (alpha-GalCer) is a known agonist of iNKT cells and it is believed that its fucosyl counterpart might have similar immunogenic properties.The key challenge in the synthesis of the target molecules involved the stereoselective synthesis of the alpha-glycosidic linkage.Of the methods examined, the per-TMS-protected glycosyl iodide donor was completely alpha-selective, and could be scaled up to provide gram quantities of the azide precursor 11, from which a range of N-acylated alpha-L-fucosyl ceramides were readily obtained and evaluated for ex vivo expansion of human iNKT cells.

View Article: PubMed Central - PubMed

Affiliation: School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.

Show MeSH
Related in: MedlinePlus