Synthesis of 7-aza- and 7-thiasphingosines, and evaluation of their interaction with sphingosine kinases and with T-cells.
The synthesis of 7-oxasphingosine (3) and 7-oxaceramide (4) was improved by starting from the 4-methoxybenzyl-protected d-galactal 9. The sphingosine analogues 5-7 and 24 were synthesized via the azido alcohol 13. The 7-thiasphingosine 5 is a poorer substrate for both isoforms of sphingosine kinase (SPHK) than sphingosine, but showed a slight preference for SPHK2. The sulfone 6 and the 7-aza compounds 7 and 24 were not phosphorylated by either SPHK1 or SPHK2, and none of 5-7 and 24 activated invariant natural killer T (iNKT) cell clones when presented by human CD1d-transfected antigen-presenting cells (APC) or by plate-bound human CD1d. Only 7 and 24 associated with plate-bound recombinant CD1d prevented stimulation of iNKT cells by alpha-galactosylceramide (alpha-GalCer).
Mathew
Thresen
T
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich.
Billaud
Célia
C
Billich
Andreas
A
Cavallari
Marco
M
Nussbaumer
Peter
P
De Libero
Gennaro
G
Vasella
Andrea
A
D000938:Antigen-Presenting Cells / Q000276:immunology; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D006801:Humans; D055611:Natural Killer T-Cells / Q000276:immunology*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000737:chemistry* / Q000378:metabolism; D020033:Protein Isoforms / Q000737:chemistry / Q000378:metabolism; D013110:Sphingosine / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000099157:Sphingosine Kinase
D055610:Antigens, CD1d; D002518:Ceramides; D017853:Phosphotransferases (Alcohol Group Acceptor); D020033:Protein Isoforms; D013110:Sphingosine; D000099157:Sphingosine Kinase; C526877:CD1D protein, human