Synthesis and biological evaluation of ceramide analogues with substituted aromatic rings or an allylic fluoride in the sphingoid moiety

The biological activity of synthetic ceramide analogues, having modified sphingoid and N-acyl chains, as well as fluorine substituents in the allylic position, was investigated in hippocampal neurons. Their influence on axonal growth was compared to that of C-6-N-acyl analogues of natural ceramides. D-erythro-Ceramides with a phenyl group in the sphingoid moiety and a short N-acyl chain were able to reverse the inhibitory effect of fumonisin B-1 (FB1), but not of D-threo-1-phenyl-2-dccanoylamino-3-morpholino-1-propanol (PDMP), on accelerated axonal growth in hippocampal neurons. Moreover, we demonstrated that a ceramide analogue with an aromatic ring in the sphingoid moiety is recognized as a substrate by glucosylceramide synthase, which suggests that the observed biological effects are mediated by activation of the ceramide analogue via glucosylation Introduction of a methyl, pentyl, fluoro, or methoxy substituent in the para position of the phenyl ring in the sphingoid moiety yielded partly active compounds. Likewise, substitution of the benzene ring for a thienyl group did not abolish the ability to reverse the inhibition of accelerated axonal growth by FB1. Both D-erythro-and L-threo-ceramide analogues, having an allylic fluorine substituent, partly reversed the FB1 inhibition.