title: 3-Deoxy-3,4-dehydro analogs of XM462. Preparation and activity on sphingolipid metabolism and cell fate.
abstract: Three analogs of the dihydroceramide desaturase inhibitor XM462 are reported. The compounds inhibit both dihydroceramide desaturase and acid ceramidase, but with different potencies depending on the N-acyl moiety. Other enzymes of sphingolipid metabolism, such as neutral ceramidase, acid sphingomyelinase, acid glucosylceramide hydrolase, sphingomyelin synthase and glucosylceramide synthase, are not affected. The effect on the sphingolipidome of the two best inhibitors, namely (R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)octanamide (RBM2-1B) and (R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)pivalamide (RBM2-1D), is in accordance with the results obtained in the enzyme assays. These two compounds reduce cell viability in A549 and HCT116 cell lines with similar potencies and both induced apoptotic cell death to similar levels than C8-Cer in HCT116 cells. The possible therapeutic implications of the activities of these compounds are discussed.
authors.affiliation: Research Unit on Bioactive Molecules, Department of Biomedicinal Chemistry, Institute for Advanced Chemistry of Catalonia, Spanish Council for Scientific Research, Jordi Girona 18-26, 08034 Barcelona, Spain.
authors.forename: Luz
authors.initials: L
authors.lastname: Camacho
authors.forename: Fabio
authors.initials: F
authors.lastname: Simbari
authors.forename: Maria
authors.initials: M
authors.lastname: Garrido
authors.forename: José Luis
authors.initials: JL
authors.lastname: Abad
authors.forename: Josefina
authors.initials: J
authors.lastname: Casas
authors.forename: Antonio
authors.initials: A
authors.lastname: Delgado
authors.forename: Gemma
authors.initials: G
authors.lastname: Fabriàs
mesh_terms: D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D002518:Ceramides / Q000737:chemistry*; D003110:Colonic Neoplasms / Q000473:pathology; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D005231:Fatty Acids, Unsaturated / Q000138:chemical synthesis / Q000494:pharmacology; D045325:HCT116 Cells; D006801:Humans; D008175:Lung Neoplasms / Q000473:pathology; D015394:Molecular Structure; D010088:Oxidoreductases / Q000037:antagonists & inhibitors*; D013107:Sphingolipids / Q000378:metabolism; D013440:Sulfides / Q000737:chemistry*
chemical_list: C574152:(R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)octanamide; C574131:(R,E)-N-(1-hydroxy-4-(tridecylthio)but-3-en-2-yl)pivalamide; D000577:Amides; D000970:Antineoplastic Agents; D002518:Ceramides; D004791:Enzyme Inhibitors; D005231:Fatty Acids, Unsaturated; D013107:Sphingolipids; D013440:Sulfides; C530382:XM 462; D010088:Oxidoreductases; C108138:dihydroceramide desaturase