title: Synthesis and biological activity of a novel inhibitor of dihydroceramide desaturase.
abstract: A novel mechanism-based dihydroceramide desaturase inhibitor (XM462) in which the substrate C5 methylene group is replaced by a sulfur atom is reported. Dihydroceramide desaturase inhibition occurred both in vitro and in cultured cells with IC(50) values of 8.2 and 0.78 microM, respectively, at a substrate concentration of 10 microM. In vitro experiments showed that XM462 produced a mixed-type inhibition (K(i)=2 microM, alpha=0.83). LC-MS analyses showed that accumulation of endogenous dihydroceramides occurred in cells upon treatment with XM462 in serum-free medium, whereas ceramides built up in controls. In addition, XM462 was found to be metabolised to its 1-glucosyl and 1-phosphocholine derivatives, and to the products of N-deacylation and reacylation with palmitoyl and stearoyl groups. In Jurkat A3 cells cultured in serum-free medium, viability, as the percentage of trypan blue unstained cells in total cells, was reduced upon XM462 treatment (5 microM, 24 h), but not in controls. The interest of this compound is discussed.
authors.affiliation: Research Unit on BioActive Molecules, Departamento de Química Orgánica Biológica, Instituto de Investigaciones Químicas y Ambientales de Barcelona, CSIC, Jordi Girona 18, 08034 Barcelona, Spain.
authors.forename: Jose M
authors.initials: JM
authors.lastname: Munoz-Olaya
authors.forename: Xavier
authors.initials: X
authors.lastname: Matabosch
authors.forename: Carmen
authors.initials: C
authors.lastname: Bedia
authors.forename: Meritxell
authors.initials: M
authors.lastname: Egido-Gabás
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
mesh_terms: D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D019169:Jurkat Cells; D008862:Microsomes, Liver / Q000187:drug effects / Q000201:enzymology; D008968:Molecular Conformation; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D051381:Rats; D013237:Stereoisomerism; D013440:Sulfides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors
chemical_list: D002518:Ceramides; D004791:Enzyme Inhibitors; D013440:Sulfides; C530382:XM 462; D010088:Oxidoreductases; C108138:dihydroceramide desaturase