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) (FB(1)), but not of D-threo-1-phenyl-2-decanoylamino-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 FB(1). Both D-erythro- and L-threo-ceramide analogues, having an allylic fluorine substituent, partly reversed the FB(1) inhibition.
Van Overmeire
I
I
Laboratory for Medicinal Chemistry (FFW), Ghent University, Harelbekestraat 72, B-9000 Ghent, Belgium.
Boldin
S A
SA
Venkataraman
K
K
Zisling
R
R
De Jonghe
S
S
Van Calenbergh
S
S
De Keukeleire
D
D
Futerman
A H
AH
Herdewijn
P
P
D000498:Allyl Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D001369:Axons / Q000187:drug effects / Q000502:physiology; D002264:Carboxylic Acids / Q000037:antagonists & inhibitors; D002478:Cells, Cultured; D002518:Ceramides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D037341:Fumonisins; D005964:Glucosyltransferases / Q000378:metabolism; D006056:Golgi Apparatus / Q000201:enzymology; D006624:Hippocampus / Q000648:ultrastructure; D008099:Liver / Q000648:ultrastructure; D051381:Rats; D017208:Rats, Wistar; D013237:Stereoisomerism; D013329:Structure-Activity Relationship
D000498:Allyl Compounds; D002264:Carboxylic Acids; D002518:Ceramides; D037341:Fumonisins; C056933:fumonisin B1; D005964:Glucosyltransferases; C023246:ceramide glucosyltransferase