Analogs of the dihydroceramide desaturase inhibitor GT11 modified at the amide function: synthesis and biological activities |
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Authors: | Bedia Carmen Triola Gemma Casas Josefina Llebaria Amadeu Fabriàs Gemma |
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Affiliation: | 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. |
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Abstract: | 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. |
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