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Título : Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities
Autor : Bedia Girbés, Carmen, Triola Guillem, Gemma, Casas Brugulat, Josefina, Llebaria Soldevilla, Amadeu, Fabriàs, Gemma
Palabras clave : Dihydroceramide desaturase
Inhibitor GT11
De novo biosynthesis
Fecha de publicación : 8-Sep-2005
Editor: Royal Society of Chemistry (Great Britain)
Resumen: Dihydroceramide 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.
Descripción : 6 pages, 3 figures, 2 schemes, 1 table.-- PMID: 16211106 [PubMed].-- Printed version published Sep 2005.
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ISSN: 1477-0520 (Print)
1477-0539 (Online)
DOI: 10.1039/b510198k
Citación : Organic and Biomolecular Chemistry 3(20): 3707-3712 (2005)
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