Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N- oleoylethanolamine analogues

16 pages, 3 figures, 2 schemes.-- PMID: 16942762 [PubMed].-- Printed version published Oct 2006.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.Partial financial support from Ministerio de Ciencia y Tecnología (Spain) (Projects MCYT BQU2002-03737 and CTQ2005-00175/BQU) and Fondos Feder (EU), Fundación Ramón Areces, Fundació La Marató de TV3 (Projects 040730 and 040731) and Generalitat de Catalunya (Projects 2005SGR01063) is acknowledged. CB, SG, and OR are also acknowledged to Ministerio de Educación y Ciencia (Spain), CSIC, and Generalitat de Catalunya, respectively, for predoctoral fellowships; GT thanks Genzyme for partial support of a CSIC-I3P contract.Peer reviewe