Synthesis and Evaluation of Sphingolipid Analogues

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 α ‐galactosylceramide ( α ‐GalCer) to plate‐bound human CD1d and subsequent T‐cell response to α ‐GalCer. Only 15 reduced activation by α ‐GalCer significantly and independently of the cytokine measured.