Synthesis and evaluation of sphingolipid analogues: modification of the hydroxy group at C(1) of 7-oxasphingosine, and of the hydroxy group at C(1) and the amide group of 7-oxaceramides.
The analogues 7-9 of 7-oxaceramide and 7-oxasphingosine were synthesized from the known azidosphingosine 21. The 1,4-disubstituted 1,2,3-triazole analogues 10-16 of ceramides were synthesized by the click reaction of the known azide 24. None of the analogues 7-15 was active as inhibitor of SPHK type 1 and of acid sphingomyelinase, whereas 16 is a weak inhibitor of SPHK1. Triazoles 10, 11, and 15 did not inhibit ceramide phosphorylation by CerK, and none of 7, 8, and 10-15 activated invariant natural killer T (iNKT) cell clones when presented by human CD1d-transfected antigen-presenting cells (APC) or by plate-bound human CD1d [55]. Triazoles 14 and 15 prevent binding of alpha-galactosylceramide (alpha-GalCer) to plate-bound human CD1d and subsequent T-cell response to alpha-GalCer. Only 15 reduced activation by alpha-GalCer significantly and independently of the cytokine measured.
Mathew
Thresen
T
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH-Zürich, Wolfgang-Pauli-Strasse 10, Zürich.
Billich
Andreas
A
Cavallari
Marco
M
Bornancin
Frederic
F
Nussbaumer
Peter
P
De Libero
Gennaro
G
Vasella
Andrea
A
D000938:Antigen-Presenting Cells / Q000276:immunology / Q000378:metabolism; D055610:Antigens, CD1d / Q000235:genetics / Q000276:immunology; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry*; D006801:Humans; D055611:Natural Killer T-Cells / Q000276:immunology / Q000378:metabolism; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000099157:Sphingosine Kinase
D055610:Antigens, CD1d; D002518:Ceramides; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D000099157:Sphingosine Kinase; C526877:CD1D protein, human