Article

Synthesis of the tetrasaccharide residue of clarhamnoside, a novel glycosphingolipid isolated from the marine sponge Agelas clathrodes

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Abstract

A tetrasaccharide, alpha-l-Rhap-(1-->3)-beta-d-GalpNAc-(1-->6)-alpha-d-Galp-(1-->2)-alpha-d-Galp, the carbohydrate moiety of clarhamnoside isolated from the marine sponge Agelas clathrodes, was synthesized as its propyl glycoside via a convergent approach. The key steps to the synthetic strategy were the stereoselective construction of the reducing-end disaccharide alpha-d-Galp-(1-->2)-d-Galp (5) and efficient coupling with the terminal disaccharide alpha-l-Rhap-(1-->3)-d-GalpNAc building block, in which the N-phthalimido-protected trifluoroacetimidate 13 was proved to be an effective donor.

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... For this, PTFA donors have betrayed outstanding glycosylation properties in the synthesis of N-glycosides of peptides which contain asparagine [19,69]. Furthermore, PTFA donors have found applications in the synthesis of many other glycoconjugates and oligosaccharides [70,71]. ...
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Toralactone 9-O-beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranosyl-(1-->3)-beta-d-glucopyranosyl-(1-->6)-beta-d-glucopyranoside (1, cassiaside C(2)), isolated from Cassia obtusifolia L. and showing strong antiallergic activity, was concisely synthesized employing glycosyl trifluoroacetimidates as glycosylation agents. The unique naphtho-alpha-pyrone structure of toralactone (5) was constructed by condensation of orsellinate 8 with pyrone 9 in the presence of LDA as developed by Staunton and co-workers. The naphthol of toralactone showed minimal reactivity as an acceptor and was screened with various glycosyl donors. It is finally concluded that sacrifice of an excess amount of the trifluoroacetimidate or trichloroacetimidate donors (6f/6g, 6.0 equiv) in the presence of a catalytic amount of TMSOTf (0.05 and 0.3 equiv, respectively) afforded excellent yields of the coupling product, which was otherwise only a minor product under a variety of conditions examined.
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OCH, a synthetic analog of alpha-galactosylceramide with a truncated sphingosine chain, stimulates natural killer T (NKT) cells to produce predominantly Th2 cytokines. Thus, OCH may be a potential agent for the treatment of Th1-mediated autoimmune diseases. This study was designed to evaluate the protective effects of OCH on collagen-induced arthritis (CIA) in mice. Mice were immunized with type II collagen (CII) and injected intraperitoneally twice per week with OCH, before or after the onset of CIA. They were monitored to assess the effect of OCH treatment on the severity of disease. Anti-CII antibodies and cytokine production were measured by enzyme-linked immunosorbent assay. Expression of cytokine genes was determined by quantitative reverse transcriptase-polymerase chain reaction. OCH inhibited CIA in wild-type C57BL/6 (B6) mice but not in NKT-deficient mice. OCH suppressed CIA in SJL mice, which are prone to autoimmune diseases and have a deficiency in the number and function of NKT cells which is similar to that in patients with autoimmune diseases, even after disease has already developed. Disease protection conferred by OCH correlated with its ability to selectively induce Th2 cytokine production mediated by NKT cells and to promote collagen-specific Th2 responses. Neutralization of interleukin-4 (IL-4) or IL-10 with monoclonal antibodies abolished disease protection by OCH, indicating a critical role for these cytokines. Taken together, our findings suggest that OCH holds possibilities as a therapeutic agent for autoimmune diseases such as rheumatoid arthritis.
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Reinvestigation of the glycosphingolipid composition of the marine sponge Agelas clathrodes revealed the presence of a new tetraglycosylated alpha-galactoglycosphingolipid (1a), containing an unusual l-rhamnose unit in the sugar head. The structure of the new compound was elucidated using extensive 2D NMR studies. Because of the strong overlapping of the signals of the sugar protons in the (1)H spectrum, (13)C-coupled and (13)C-decoupled phase-sensitive HMQC spectra were used to study the multiplicity of the overlapping signals. In addition, the absolute configuration of sugars was determined using a simple and efficient, yet underutilized CD method.
Article
Non-obese diabetic (NOD) mice develop diabetes mediated by pathogenic T-helper type 1 (Th1) cells. V alpha 14 Natural killer (NKT) cells are a unique lymphocyte subtype implicated in the regulation of autoimmunity and a good source of protective Th2 cytokines. We recently developed a Th2-skewing NKT cell ligand, OCH. OCH, a sphingosine truncated derivative of alpha-galactosylceramide (alpha-GC), stimulates NKT cells to selectively produce Th2 cytokines. Here we show that OCH prevented the development of diabetes and insulitis in NOD mice. The suppression of insulitis by OCH was more profound compared to alpha-GC. Infiltration of T cells, B cells and macrophages into islets is inhibited in OCH-treated NOD mice. OCH-mediated suppression of diabetes is associated with Th2 bias of anti-islet antigen response and increased IL-10 producing cells among islet-infiltrating leukocytes. Considering the non-polymorphic and well conserved features of the CD1d molecule in mice and humans, these findings not only support the proposed role of NKT cells in the regulation of self-tolerance but also highlight the potential use of OCH for therapeutic intervention in type I diabetes.
Article
Two novel hybrid molecules 3-O-sulfo-alpha/beta-galactosylceramide 3 and 4, which are derived from an immunostimulatory agent alpha-GalCer 1 and self-glycolipid ligand sulfatide 2, were designed and synthesized. Compound 3 was shown to efficiently stimulate human NKT cells to secret IL-4 and IFN-gamma, with activities similar to 1, suggesting that modification of the 3''-OH position of the galactose moiety with sulfate has no significant effect on NKT cell stimulation. As a comparison, the beta-isomer 4 has no affinity to NKT cells, which demonstrates that the alpha-glycosidic bond of galactosylceramide is crucial to the NKT cells activation.
Article
Alpha-galactoglycosphingolipids (alpha-GalGSLs) are unique immunostimulatory glycosphingolipids from marine sponges. Analysis of the glycosphingolipid composition of the marine sponge Axinella damicornis revealed the presence of a new alpha-GalGSL, damicoside (3a), which is the first alpha-GalGSL with a glycosylated galactose 4-OH group. Structure elucidation of damicoside was performed using spectroscopic and chemical methods. When tested in a spleen cell proliferation assay, 3a exhibited a stimulatory activity comparable to that of agelasphin (2), showing that a free galactose 4-OH group is not essential for the immunostimulatory activity of alpha-GalGSLs and providing a further step toward the complete understanding of their structure-activity relationship.
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(a) Douglas, N. L.; Ley, S. V.; Lü cking, U.; Warriner, S. L. J. Chem. Soc., Perkin. Trans. 1 1998, 51–65; (b) Smid, P.; de Ruiter, G. A.; van der Marel, G. A.; Rombouts, F. M.; van Boons, J. H. J. Carbohydr. Chem. 1991, 10, 833–849.
OCH 2 CH 2 CH 3 ); 13 C NMR (D 2 O): d 174
  • Hz
Hz), 2.05 (s, 3H, COCH 3 ), 1.63 (m, 2H, OCH 2 CH 2 CH 3 ), 1.27 (d, 3H, J 6.4 Hz, CH 3 -6 IV ), 0.92 (dd, 3H, J 7.7, 7.0 Hz, OCH 2 CH 2 CH 3 ); 13 C NMR (D 2 O): d 174.6 (COCH 3 ), 102.3 (C-1 IV ), 101.2 (C-1 III ), 96.3 (C-1 II ), 95.4 (C-1 I ), 78.9, 75.2, 72.9, 71.9, 70.9, 70.4, 70.0, 69.9, 69.5, 69.3, 69.1, 69.0, 68.2, 68.1, 67.7, 61.2, 60.9, 51.6, 22.2 (COCH 3 ), 22.0 (OCH 2 CH 2 CH 3 ), 16.7 (CH 3 -6 IV ), 10.0 (OCH 2 CH 2 CH 3 ). HRMS: calcd
  • D Wu
  • G W Xing
  • M A Poles
  • A Horowitz
  • Y Kinjo
  • B Sullivan
  • V Bodmer-Narkevitch
  • O Plettenburg
  • M Tsuji
  • D D Ho
  • C H Wong
Wu, D.; Xing, G. W.; Poles, M. A.; Horowitz, A.; Kinjo, Y.; Sullivan, B.; Bodmer-Narkevitch, V.; Plettenburg, O.; Tsuji, M.; Ho, D. D.; Wong, C. H. Proc. Natl. Acad. Sci. U.S.A. 2005, 102, 1351-1356.
  • N L Douglas
  • S V Ley
  • U Lü Cking
  • S L Warriner
  • P Smid
  • G A De Ruiter
Douglas, N. L.; Ley, S. V.; Lü cking, U.; Warriner, S. L. J. Chem. Soc., Perkin. Trans. 1 1998, 51-65; (b) Smid, P.; de Ruiter, G. A.; van der Marel, G. A.; Rombouts, F. M.; van Boons, J. H. J. Carbohydr. Chem. 1991, 10, 833-849.
  • Douglas