3-Deoxy-3,4-dehydro analogs of XM462. Preparation and activity on sphingolipid metabolism and cell fate
Autor: | Fabio Simbari, Gemma Fabriàs, Luz Camacho, Josefina Casas, Maria Del Mar Capeans Garrido, Antonio Delgado, José Luis Abad |
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Rok vydání: | 2012 |
Předmět: |
Lung Neoplasms
Cell Survival Stereochemistry Clinical Biochemistry Pharmaceutical Science Antineoplastic Agents Apoptosis Sulfides Ceramides Biochemistry Cell Line Tumor Drug Discovery Sphingomyelin synthase medicine Humans Enzyme Inhibitors Molecular Biology chemistry.chemical_classification Sphingolipids Molecular Structure Neutral Ceramidase biology Organic Chemistry Dihydroceramide desaturase HCT116 Cells Ceramidase Amides Sphingolipid Acid Ceramidase Enzyme chemistry Colonic Neoplasms Fatty Acids Unsaturated biology.protein Molecular Medicine Acid sphingomyelinase Oxidoreductases medicine.drug |
Zdroj: | Bioorganic & Medicinal Chemistry. 20:3173-3179 |
ISSN: | 0968-0896 |
DOI: | 10.1016/j.bmc.2012.03.073 |
Popis: | 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. |
Databáze: | OpenAIRE |
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