Synthesis of 7-oxasphingosine and -ceramide analogues and their evaluation in a model for apoptosis.

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.