Issue 20, 2005

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

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

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

Article information

Article type
Paper
Submitted
18 Jul 2005
Accepted
08 Aug 2005
First published
08 Sep 2005

Org. Biomol. Chem., 2005,3, 3707-3712

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

C. Bedia, G. Triola, J. Casas, A. Llebaria and G. Fabriàs, Org. Biomol. Chem., 2005, 3, 3707 DOI: 10.1039/B510198K

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements