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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
Author(s) -
Mathew Thresen,
Cavallari Marco,
Billich Andreas,
Bornancin Frederic,
Nussbaumer Peter,
De Libero Gennaro,
Vasella Andrea
Publication year - 2009
Publication title -
chemistry and biodiversity
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.427
H-Index - 70
eISSN - 1612-1880
pISSN - 1612-1872
DOI - 10.1002/cbdv.200900045
Subject(s) - ceramide , sphingosine , chemistry , stereochemistry , sphingosine kinase 1 , lipid signaling , kinase , sphingolipid , cd1d , biochemistry , receptor , sphingosine 1 phosphate , natural killer t cell , apoptosis , cytotoxic t cell , in vitro
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 CD1dlipidT‐cell receptor complex.