Por favor, use este identificador para citar o enlazar a este item:
http://hdl.handle.net/10261/20245
COMPARTIR / EXPORTAR:
SHARE CORE BASE | |
Visualizar otros formatos: MARC | Dublin Core | RDF | ORE | MODS | METS | DIDL | DATACITE | |
Título: | Synthesis of cyclopropene analogues of ceramide and their effect on dihydroceramide desaturase |
Autor: | Triola Guillem, Gemma CSIC ORCID; Fabriàs, Gemma CSIC ORCID ; Casas, Josefina CSIC ORCID ; Llebaria, Amadeu CSIC ORCID | Palabras clave: | Biosynthesis of ceramide Dihydroceramide desaturase |
Fecha de publicación: | 3-dic-2003 | Editor: | American Chemical Society | Citación: | Journal of Organic Chemistry 68(26): 9924-9932 (2003) | Resumen: | The synthesis of several analogues of the N-[(1R,2S)-2-hydroxy-1-hydroxymethyl-2-(2-tridecyl-1-cyclopropenyl)ethyl]octanamide (GT11), the first reported inhibitor of dihydroceramide desaturase, as well as their effects on this enzyme, are described. Modifications of the parent structure include variations on the cyclopropene ring, the N-acyl chain length, the configuration of the stereocenters, and the hydroxyl group at C1. The key intermediates for the synthesis are the products resulting from the addition of suitable organolithium compounds to either Garner's aldehyde or its enantiomer. The final products are obtained by TMSTf-induced cleavage of the protecting groups and N-acylation, both under specific conditions. An alternative method for N-Boc deprotection is also reported that allows us to obtain the cyclopropene analogue of sphingosine 12a, which can be transformed into GT11 upon acylation. The procedure consists of the conversion of the Garner aldehyde addition products into the bicyclic dihydrooxazolo[3,4,0]oxazol-3-ones 19 by transesterification in basic medium of the tert-butyl group with the hydroxyl function at C3. Mild cleavage of the N,O-isopropylidene cyclic acetal present in 19 affords the oxazolidin-2-one 20, which gives 12a upon saponification. Furthermore, compound 20 is also the key intermediate in the synthesis of the terminal deoxy, methoxy, and fluoro derivatives 9, 10, and 11, respectively. Determination of dihydroceramide desaturase activity in vitro showed that GT11 was a competitive inhibitor (Ki = 6 μM) and that its analogues with N-hexanoyl (6) and N-decanoyl (7) moieties inhibited the enzyme with similar potencies (IC50 = 13 and 31 μM, respectively). No decrease in dihydroceramide desaturase activity was observed with any of the other compounds tested. | Descripción: | 9 pages, 3 figures, 6 schemes, 2 charts.-- PMID: 14682684 [PubMed].-- Printed version published Dec 26, 2003.-- Supporting information available at: http://pubs.acs.org/doi/suppl/10.1021/jo030141u | Versión del editor: | http://dx.doi.org/10.1021/jo030141u | URI: | http://hdl.handle.net/10261/20245 | DOI: | 10.1021/jo030141u | ISSN: | 0022-3263 | E-ISSN: | 1520-6904 |
Aparece en las colecciones: | (IQAC) Artículos |
Mostrar el registro completo
CORE Recommender
SCOPUSTM
Citations
57
checked on 22-abr-2024
WEB OF SCIENCETM
Citations
54
checked on 23-feb-2024
Page view(s)
449
checked on 24-abr-2024
Google ScholarTM
Check
Altmetric
Altmetric
NOTA: Los ítems de Digital.CSIC están protegidos por copyright, con todos los derechos reservados, a menos que se indique lo contrario.