New CD1d agonists: synthesis and biological activity of 6″-triazole-substituted α-galactosyl ceramides.
Huisgen [3+2] dipolar cycloaddition of 6″-azido-6″-deoxy-α-galactosyl ceramide 11 with a range of alkynes (or a benzyne precursor) yielded a series of triazole-containing α-galactosyl ceramide (α-GalCer) analogues in high yield. These α-GalCer analogues and the precursor azide 11 were tested for their ability to activate iNKT cells and stimulate IL-2 cytokine secretion in vitro, and IFN-γ and IL-4 cytokine secretion in vivo. Some of these analogues, specifically 11, 12b, 12f and 13, were more potent IL-2 stimulators than the prototypical CD1d agonist, α-GalCer 1. In terms of any cytokine bias, most of the triazole-containing analogues exhibited a small Th2 cytokine-biasing response relative to that shown by α-GalCer 1. In contrast, the cycloaddition precursor, namely azide 11, provided a small Th1 cytokine-biasing response.
School of Biosciences, University of Birmingham, Edgbaston, Birmingham B15 2TT, UK.
Peter J
PJ
Jervis
Lisa M
LM
Graham
Erin L
EL
Foster
Liam R
LR
Cox
Steven A
SA
Porcelli
Gurdyal S
GS
Besra
D000818:Animals; D055610:Antigens, CD1d / Q000737:chemistry* / Q000378:metabolism; D002460:Cell Line; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006825:Hybridomas / Q000378:metabolism; D007274:Injections, Intraperitoneal; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000378:metabolism; D015847:Interleukin-4 / Q000097:blood; D051379:Mice; D055611:Natural Killer T-Cells / Q000187:drug effects / Q000276:immunology / Q000378:metabolism; D014230:Triazoles / Q000737:chemistry*
D055610:Antigens, CD1d; D005699:Galactosylceramides; D007376:Interleukin-2; D014230:Triazoles; C493154:alpha-galactosylceramide; D015847:Interleukin-4; D007371:Interferon-gamma