Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities.
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.
Bedia
Carmen
C
Research Unit on BioActive Molecules (RUBAM), Department of Biological Organic Chemistry, Instituto de Investigaciones Químicas y Ambientales de Barcelona (IIQAB), CSIC Jordi Girona 18, 08034, Barcelona, Spain.
Triola
Gemma
G
Casas
Josefina
J
Llebaria
Amadeu
A
Fabriàs
Gemma
G
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D000581:Amidohydrolases / Q000037:antagonists & inhibitors; D055572:Ceramidases; D003521:Cyclopropanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000577:Amides; D003521:Cyclopropanes; D004791:Enzyme Inhibitors; C497935:N-((1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl)octanamide; D010088:Oxidoreductases; C108138:dihydroceramide desaturase; D000581:Amidohydrolases; D055572:Ceramidases