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Title: Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N- oleoylethanolamine analogues
Authors: Grijalvo, Santiago, Bedia Girbés, Carmen, Triola Guillem, Gemma, Casas Brugulat, Josefina, Llebaria Soldevilla, Amadeu, Teixidó, Jordi, Rabal, Obdulia, Levade, Thierry, Delgado Cirilo, Antonio, Fabriàs, Gemma
Keywords: Sphingolipids
Ceramide
Farber disease
Ceramidase
Inhibitor
Issue Date: 7-Aug-2006
Publisher: Elsevier
Abstract: The synthesis of novel N-acylethanolamines and their use as inhibitors of the aCDase is reported here. The compounds are either 2-oxooctanamides or oleamides of sphingosine analogs featuring a 3-hydroxy-4,5-hexadecenyl tail replaced by ether or thioether moieties. It appears that, within the 2-oxooctanamide family, the C3–OH group of the sphingosine molecule is required for inhibition both in vitro and in cultured cells. Furthermore, although the (E)-4 double bond is not essential for inhibitory activity, the (E) configuration is required, since the analogue with a (Z)-4 unsaturation was not inhibitory. None of the oleamides inhibited the aCDase in vitro. Conversely, with the exception of N-oleoylethanolamine and its analogs with S-decyl and S-hexadecyl substituents, all the synthesized oleamides inhibited the aCDase in cultured cells, although with a relatively low potency. We conclude that novel aCDase inhibitors can evolve from N-acylation of sphingoid bases with electron deficient-acyl groups. In contrast, chemical modification of the N-oleoylsphingosine backbone does not seem to offer an appropriate strategy to obtain aCDase inhibitors.
Description: 16 pages, 3 figures, 2 schemes.-- PMID: 16942762 [PubMed].-- Printed version published Oct 2006.
Publisher version (URL): http://dx.doi.org/10.1016/j.chemphyslip.2006.07.001
URI: http://hdl.handle.net/10261/12455
ISSN: 0009-3084
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Citation: Chemistry and Physics of Lipids 144(1): 69-84 (2006)
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