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.
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.
Laboratorium für Organische Chemie, Departement Chemie und Angewandte Biowissenschaften, ETH Zürich, Wolfgang-Pauli-Strasse 10, CH-8093 Zürich.
Thresen
T
Mathew
Marco
M
Cavallari
Andreas
A
Billich
Frederic
F
Bornancin
Peter
P
Nussbaumer
Gennaro
G
De Libero
Andrea
A
Vasella
D055610:Antigens, CD1d / Q000276:immunology / Q000378:metabolism; D002518:Ceramides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D016207:Cytokines / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D006801:Humans; D050356:Lipid Metabolism / Q000276:immunology / Q000502:physiology; D008956:Models, Chemical; D008968:Molecular Conformation; D055611:Natural Killer T-Cells / Q000166:cytology / Q000187:drug effects* / Q000276:immunology; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors* / Q000378:metabolism; D010880:Piperidines / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D011948:Receptors, Antigen, T-Cell / Q000276:immunology / Q000378:metabolism; D000099157:Sphingosine Kinase
D055610:Antigens, CD1d; D002518:Ceramides; D016207:Cytokines; D004791:Enzyme Inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor); D010880:Piperidines; D011948:Receptors, Antigen, T-Cell; D000099157:Sphingosine Kinase; C066324:ceramide kinase