Synthesis and Evaluation of 1,2,3-Triazole Containing Analogues of the Immunostimulant α-GalCer

Abstract

alpha-GalCer is the first defined and most potent agonistic antigen of the T cell receptor of natural killer T cells. We have prepared a series of 1,2,3-triazole-containing alpha-GalCer analogues in which the lipid chain lengths have been incrementally varied. We found that this isosteric replacement of alpha-GalCer's amide moiety with triazole increases the IL-4 versus IFN-gamma bias of released cytokines. The stimulatory effect was influenced by the length of the attached chain. In particular, the long-chained triazole analogues have a comparable stimulatory effect on cytokine production as alpha-GalCer and exhibit a stronger Th2 cytokine response.

Click Chemistry: 1,2,3‐Triazoles as Pharmacophores

“…Lee et al prepared a series of 1,2,3-triazole-containing a-GalCer analogues (Scheme 3, 4) in which the lipid chain lengths were incrementally varied. [61] Isosteric replacement of the amide moiety of a-GalCer with a triazole increased the IL-4 versus IFN-g bias of released cytokines. The stimulatory effect was influenced by the length of the attached chain; the long-chained 1,2,3-triazole analogues showed comparable stimulatory effect on cytokine production as a-GalCer and exhibit a stronger Th2 cytokine response.…”

Synthesis of a-O- and a-S-Glycosphingolipids Related to Sphingomonous cell Wall Antigens Using Anomerisation

“…The triazole proton of the minor regioisomer 31 is more remote from the dihydroceramide chain, and as would be expected for this isomer there was not any NOE cross-peaks observed between this proton and the dihydroceramide chain. The regioselectivity of this Cu(I) promoted cycloaddition reaction was not as high as that reported for the previously synthesised triazole containing glycolipids, were the 1,4 isomer was not reported [19]. The protecting groups were removed from 30/31 to give a mixture of triazoles (52%) where 10 was the major component (ratio of 1,4 to 1,5-isomer, 88:12).…”

“…In recent research, a triazole was incorporated into α-GalCer analogues as an isostere of the sphingosine amide. This conferred interesting and desirable biological properties, as triazole analogues with a long alkyl chains had potent stimulatory effects on cytokine production and showed a stronger Th2 cytokine response than found for α-GalCer [19]. Therefore, we included the preparation of such a triazole analogue containing a uronic acid 10 as part of this research work.…”

Design, Synthesis, and Immunological Evaluation of Benzyloxyalkyl-Substituted 1,2,3-Triazolyl α-GalCer Analogues

“…16−18 These compounds exhibited comparable iNKT stimulatory effect with Th2 bias on mice splenocytes. 16 The triazole moiety served as a rigid linker that is more stable to hydrolysis and oxidative/reductive conditions in biological systems. In addition, two additional hydrogen bonds were reported between the Thr154 residue and the triazole moiety.…”

“…16 All of the products were purified by column chromatography with CHCl 3 /methanol as eluents, and the products were obtained in quantitative yields.…”