Synthesis and evaluation of sphinganine analogues of KRN7000 and OCH

Rachel M. Ndonye, Douglas P. Izmirian, Matthew F. Dunn, Karl O.A. Yu, Steven A. Porcelli, Archana Khurana, Mitchell Kronenberg, Stewart K. Richardson, Amy R. Howell

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81 Scopus citations

Abstract

The phytosphingosine-containing α-galactosylceramides (α-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 α-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 TH2 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 IFNγ. 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.

Original languageEnglish (US)
Pages (from-to)10260-10270
Number of pages11
JournalJournal of Organic Chemistry
Volume70
Issue number25
DOIs
StatePublished - Dec 9 2005

ASJC Scopus subject areas

  • Organic Chemistry

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    Ndonye, R. M., Izmirian, D. P., Dunn, M. F., Yu, K. O. A., Porcelli, S. A., Khurana, A., Kronenberg, M., Richardson, S. K., & Howell, A. R. (2005). Synthesis and evaluation of sphinganine analogues of KRN7000 and OCH. Journal of Organic Chemistry, 70(25), 10260-10270. https://doi.org/10.1021/jo051147h