Design, synthesis and activity as acid ceramidase inhibitors of 2-oxooctanoyl and N-oleoylethanolamine analogues.
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.
Grijalvo
Santiago
S
Research Unit on Bioactive Molecules (RUBAM), Departament de Química Orgànica Biològica, Institut d'Investigacions Químiques i Ambientals de Barcelona (IIQAB-CSIC), Jordi Girona 18-26, E-08034 Barcelona, Spain.
Bedia
Carmen
C
Triola
Gemma
G
Casas
Josefina
J
Llebaria
Amadeu
A
Teixidó
Jordi
J
Rabal
Obdulia
O
Levade
Thierry
T
Delgado
Antonio
A
Fabriàs
Gemma
G
D000818:Animals; D002461:Cell Line, Transformed; D015195:Drug Design; D063388:Endocannabinoids; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D004983:Ethanolamines / Q000138:chemical synthesis*; D002517:Galactosylgalactosylglucosylceramidase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D006801:Humans; D008099:Liver / Q000737:chemistry; D008247:Lysosomes / Q000737:chemistry; D008928:Mitochondria / Q000737:chemistry; D015394:Molecular Structure; D009829:Oleic Acids / Q000737:chemistry*; D051381:Rats
D063388:Endocannabinoids; D004791:Enzyme Inhibitors; D004983:Ethanolamines; D009829:Oleic Acids; C033595:N-oleoylethanolamine; C029407:oleylamide; D002517:Galactosylgalactosylglucosylceramidase