title: Synthesis of 7-oxasphingosine and -ceramide analogues and their evaluation in a model for apoptosis.
abstract: The 7-oxasphingosine (1), 7-oxaceramide (2), the thio-oxaceramide 3, and N-methyloxaceramide 4 were synthesised from D-galactose via the building block 9. The apoptosis-inducing properties of 1-4 were compared to those of sphingosine (Sph) and ceramide (Cer) using a human neuroblastoma (SK-N-BE) and a murine-promyelocyte-derived (32d) cell line. There were no differences between 2-4 and Cer in terms of their effects on the viability of cells and their ability to trigger cell proliferation. However, in the presence of N,N-dimethylsphingosine, an inhibitor of sphingosine kinase (SPHK), Cer was more potent than thio-ceramide 3 in 32d cells, while thio-ceramide 3 was more potent and efficacious in SK-N-BE cells, where it showed an IC50 value of 3 nM compared to 100 nM for Cer. In both SK-N-BE and 32d cells, 7-oxasphingosine (1) and Sph were equally toxic, even in the presence of N,N-dimethylsphingosine.
authors.affiliation: Laboratorium für Organische Chemie, ETH-Hönggerberg, Wolfgang Pauli-Strasse 10, CH-8093 Zürich.
authors.forename: Roshini
authors.initials: R
authors.lastname: Rajan
authors.forename: Kurt
authors.initials: K
authors.lastname: Wallimann
authors.forename: Andrea
authors.initials: A
authors.lastname: Vasella
authors.forename: Deborah
authors.initials: D
authors.lastname: Pace
authors.forename: Armando A
authors.initials: AA
authors.lastname: Genazzani
authors.forename: Pier Luigi
authors.initials: PL
authors.lastname: Canonico
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Condorelli
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D045744:Cell Line, Tumor; D002518:Ceramides / Q000138:chemical synthesis* / Q000494:pharmacology; D004353:Drug Evaluation, Preclinical / Q000379:methods; D006801:Humans; D051379:Mice; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis* / Q000494:pharmacology
chemical_list: D002518:Ceramides; D013110:Sphingosine