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4,5,6-Trisubstituted piperidinones as conformationally restricted ceramide analogues: synthesis and evaluation as inhibitors of sphingosine and ceramide kinases and as NKT cell-stimulatory antigens
JournalArticle (Originalarbeit in einer wissenschaftlichen Zeitschrift)
 
ID 1193474
Author(s) Mathew,Thresen; Cavallari,Marco; Billich,Andreas; Bornancin,Frederic; Nussbaumer,Peter; De Libero,Gennaro; Vasella,Andrea
Author(s) at UniBasel De Libero, Gennaro
Year 2009
Title 4,5,6-Trisubstituted piperidinones as conformationally restricted ceramide analogues: synthesis and evaluation as inhibitors of sphingosine and ceramide kinases and as NKT cell-stimulatory antigens
Journal Chemistry & biodiversity
Volume 6
Number 10
Pages / Article-Number 1688-1715
Abstract The conformationally based piperidinone sphingosine analogues 7, 8, 15, and 16 were synthesized from allylic alcohol 34 via lactams 31 and 32. The L-arabino diol 7 and the L-ribo diol 8 were transformed into the amino alcohols 17-24. The L-gluco ceramide analogues 43, 46a, and 47, and the L-altro ceramide analogues 51a and 52 were synthesized from either 31 or 32. The L-ribo diols 8 and 16, and the amino alcohols 19 and 20 inhibit sphingosine kinase 1 (SPHK1), while the L-arabino analogues 7, 15, 17, and 18 are inactive. The L-arabino and the L-ribo dimethylamines 21-24, the L-gluco ceramide analogues 43, 46a, and 47, and the L-altro ceramide analogues 51a and 52 did not block SPHK1. Neither the L-arabino diol 7 nor the L-ribo diol 8 inhibited SPHK2 or ceramide kinase. The L-arabino diols 7 and 15 stimulate invariant natural killer T (iNKT) cells when presented by living antigen-presenting cells (APC) and also by plate-bound human CD1d, whereas the L-ribo diols 8 and 16, the L-arabino amino alcohols 17-18, and the dimethylamines 21-22 did not activate iNKT cells. The L-gluco ceramide analogues 43, 46a, and 47 had strongly stimulatory effects on iNKT cells when presented by living APC and also by plate-bound human CD1d, whereas the L-altro ceramide analogue 52 activated only weakly. All activatory compounds induced preferentially the release of pro-inflammatory cytokines, indicating the formation of a stable CD1d--lipid--T-cell receptor complex.
Publisher Helvetica Chimica Acta
ISSN/ISBN 1612-1872
edoc-URL http://edoc.unibas.ch/dok/A6003717
Full Text on edoc No
Digital Object Identifier DOI 10.1002/cbdv.200900045
PubMed ID http://www.ncbi.nlm.nih.gov/pubmed/19842132
ISI-Number WOS:000271372000004
Document type (ISI) Journal Article
 
   

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