title: Aziridine ring opening for the synthesis of sphingolipid analogues: inhibitors of sphingolipid-metabolizing enzymes.
abstract: A library of sphingolipid analogues is designed and tested as inhibitors against mammalian and fungal sphingolipid enzymes. The synthesis of sphingolipid analogues is based on the nucleophilic ring-opening reactions of N-activated aziridine derivatives with thiols, β-thioglycosyl thiols, phosphorothioates, phosphates, and amines to afford compounds having different lipid backbones and substituents representative of the naturally occurring sphingolipid families. The screening on mammalian sphingomyelin synthase (SMS) and glucosylceramide synthase (GCS) and yeast inositol phosphorylceramide synthase (IPCS) enzymes identified several inhibitors of GCS and IPCS, but no inhibition of SMS was observed among the tested compounds.
authors.affiliation: Medicinal Chemistry Laboratory (MedChemLab), Departament de Química Biomèdica, Institut de Química Avançada de Catalunya (IQAC-CSIC) , Jordi Girona 18-26, Barcelona 08034, Spain.
authors.forename: Anna
authors.initials: A
authors.lastname: Alcaide
authors.forename: Amadeu
authors.initials: A
authors.lastname: Llebaria
mesh_terms: D000818:Animals; D001388:Aziridines / Q000737:chemistry*; D005964:Glucosyltransferases / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D012441:Saccharomyces cerevisiae; D013107:Sphingolipids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D017855:Transferases (Other Substituted Phosphate Groups) / Q000037:antagonists & inhibitors* / Q000737:chemistry*
chemical_list: D001388:Aziridines; D013107:Sphingolipids; C033132:aziridine; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase; D017855:Transferases (Other Substituted Phosphate Groups); C070186:phosphatidylcholine-ceramide phosphocholine transferase