Health & Environmental Research Online (HERO)


Print Feedback Export to File
7210869 
Journal Article 
Inhibitors of specific ceramide synthases 
Schiffmann, S; Hartmann, D; Fuchs, S; Birod, K; Ferreiròs, N; Schreiber, Y; Zivkovic, A; Geisslinger, G; Grösch, S; Stark, H; , 
2012 
Yes 
Biochimie
ISSN: 0300-9084
EISSN: 1638-6183 
ELSEVIER FRANCE-EDITIONS SCIENTIFIQUES MEDICALES ELSEVIER 
ISSY-LES-MOULINEAUX 
94 
2 
558-565 
English 
21945810 
WOS:000300270900033 
Ceramide synthases (CerSs) are key enzymes in the biosynthesis of ceramides and display a group of at least six different isoenzymes (CerS1-6). Ceramides itself are bioactive molecules. Ceramides with different N-acyl side chains (C(14:0)-Cer - C(26:0)-Cer) possess distinct roles in cell signaling. Therefore, the selective inhibition of specific CerSs which are responsible for the formation of a specific ceramide holds promise for a number of new clinical treatment strategies, e.g., cancer. Here, we identified four of hitherto unknown functional inhibitors of CerSs derived from the FTY720 (Fingolimod) lead structure and showed their inhibitory effectiveness by two in vitro CerS activity assays. Additionally, we tested the substances in two cell lines (HCT-116 and HeLa) with different ceramide patterns. In summary, the in vitro activity assays revealed out that ST1058 and ST1074 preferentially inhibit CerS2 and CerS4, while ST1072 inhibits most potently CerS4 and CerS6. Importantly, ST1060 inhibits predominately CerS2. First structure-activity relationships and the potential biological impact of these compounds are discussed.