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

• Published in: Organic & biomolecular chemistry Vol. 3; no. 20; p. 3707
• Main Authors: Bedia, Carmen, Triola, Gemma, Casas, Josefina, Llebaria, Amadeu, Fabriàs, Gemma
• Format: Journal Article
• Language: English
• Published: England 21-10-2005
• Subjects: Amides - chemical synthesis; Amides - chemistry; Amides - pharmacology; Amidohydrolases - antagonists & inhibitors; Ceramidases; Cyclopropanes - chemical synthesis; Cyclopropanes - chemistry; Cyclopropanes - pharmacology; Enzyme Activation - drug effects; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - chemistry; Enzyme Inhibitors - pharmacology; Molecular Conformation; Oxidoreductases - antagonists & inhibitors; Stereoisomerism; Structure-Activity Relationship
• ISSN: 1477-0520
• DOI: 10.1039/b510198k

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 alpha-carbonyl methylene by oxygen result in inactive compounds. In contrast, both urea (3) and thiourea (4) analogs of GT11, as well as three alpha-ketoamides (5-7), did inhibit the desaturation of N-octanoylsphinganine to N-octanoylsphingosine, although with significantly lower potency than GT11. Furthermore, the alpha-ketoamides 5-7 inhibit the acidic ceramidase with similar potencies (IC50 52-83 microM). 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.