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Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities

AuthorsBedia Girbés, Carmen; Triola Guillem, Gemma; Casas Brugulat, Josefina; Llebaria, Amadeu; Fabriàs, Gemma
KeywordsDihydroceramide desaturase
Inhibitor GT11
De novo biosynthesis
Issue Date8-Sep-2005
PublisherRoyal Society of Chemistry (Great Britain)
CitationOrganic and Biomolecular Chemistry 3(20): 3707-3712 (2005)
AbstractDihydroceramide desaturase is the last enzyme in the biosynthesis of ceramide de novo. The cyclopropene-containing sphingolipid GT11 is a competitive inhibitor of dihydroceramide desaturase. The biological effects of chemical modification of the GT11 amide linkage are reported in this article. Either N-methyl substitution or replacement of the amide -carbonyl methylene by oxygen result in inactive compounds. In contrast, both urea (3) and thiourea (4) analogs of GT11, as well as three -ketoamides (5–7), did inhibit the desaturation of N-octanoylsphinganine to N-octanoylsphingosine, although with significantly lower potency than GT11. Furthermore, the -ketoamides 5–7 inhibit the acidic ceramidase with similar potencies (IC50 52–83 µM). Inhibition of the neutral/alkaline ceramidase by these compounds requires around 20-fold higher concentrations. Structure–activity relationships and the biological interest of these compounds are discussed.
Description6 pages, 3 figures, 2 schemes, 1 table.-- PMID: 16211106 [PubMed].-- Printed version published Sep 2005.
Publisher version (URL)http://dx.doi.org/10.1039/b510198k
Appears in Collections:(IQAC) Artículos
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