title: Synthesis and evaluation of sphinganine analogues of KRN7000 and OCH.
abstract: [structures: see text] The phytosphingosine-containing alpha-galactosylceramides (alpha-GalCers), KRN7000 and OCH, have been shown to activate NKT cells via interaction with CD1d, a member of the CD1 family of antigen presenting proteins. Evidence from KRN7000 stimulation of NKT cells suggests that alpha-GalCers may have applications in the treatment or prevention of a range of viral, bacterial, and autoimmune conditions. Moreover, OCH, a truncated analogue of KRN7000, appears to induce a T(H)2 bias, which could have implications for the treatment of autoimmune and inflammatory conditions. We have prepared the direct sphinganine-containing analogues of KRN7000 and OCH, 1 and 2, and found them to be comparable in activity to the parent compounds in inducing the release of IL-2, IL-4, and IFNgamma. In addition, compound 2 leads to a cytokine bias similar to that seen with OCH. This is significant because sphinganines are more easily accessed than phytosphingosines, which should facilitate SAR studies.
authors.affiliation: Department of Chemistry, University of Connecticut, Storrs, Connecticut 06269-3060, USA.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Ndonye
authors.forename: Douglas P
authors.initials: DP
authors.lastname: Izmirian
authors.forename: Matthew F
authors.initials: MF
authors.lastname: Dunn
authors.forename: Karl O A
authors.initials: KO
authors.lastname: Yu
authors.forename: Steven A
authors.initials: SA
authors.lastname: Porcelli
authors.forename: Archana
authors.initials: A
authors.lastname: Khurana
authors.forename: Mitchell
authors.initials: M
authors.lastname: Kronenberg
authors.forename: Stewart K
authors.initials: SK
authors.lastname: Richardson
authors.forename: Amy R
authors.initials: AR
authors.lastname: Howell
mesh_terms: D000818:Animals; D017951:Antigen Presentation; D002478:Cells, Cultured; D005699:Galactosylceramides / Q000138:chemical synthesis / Q000494:pharmacology*; D006017:Glycolipids / Q000138:chemical synthesis / Q000494:pharmacology*; D007371:Interferon-gamma / Q000032:analysis / Q000378:metabolism; D015847:Interleukin-4 / Q000032:analysis / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology; D013154:Spleen / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D005699:Galactosylceramides; D006017:Glycolipids; C501055:tetracosanoic acid 1-galactopyranosyloxy-3,4-dihydroxydec-2-yl amide; D015847:Interleukin-4; D007371:Interferon-gamma; D013110:Sphingosine; C005682:safingol; C103873:KRN 7000