Synthesis of Homoceramides, Novel Ceramide Analogues, and Their Lack of Effect on the Growth of Hippocampal Neurons

• Published in: Journal of organic chemistry Vol. 67; no. 3; pp. 988 - 996
• Main Authors: De Jonghe, Steven, Lamote, Inge, Venkataraman, Krishnan, Boldin, Swetlana A., Hillaert, Ulrik, Rozenski, Jef, Hendrix, Chris, Busson, Roger, De Keukeleire, Denis, Van Calenbergh, Serge, Futerman, Anthony H., Herdewijn, Piet
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.02.2002; Amer Chemical Soc
• Subjects: Animals; Cell Division - drug effects; Cells, Cultured; Ceramides - chemical synthesis; Ceramides - chemistry; Ceramides - pharmacology; Chemistry; Chemistry, Organic; Exact sciences and technology; Hippocampus - cytology; Hippocampus - drug effects; Lipids; Molecular Structure; Neurons - cytology; Neurons - drug effects; Organic chemistry; Physical Sciences; Preparations and properties; Rats; Rats, Wistar; Science & Technology; Spectrum Analysis; SIGNAL-TRANSDUCTION; GLUCOSYLCERAMIDE SYNTHESIS; ENANTIOSELECTIVE SYNTHESIS; AMINO-ACIDS; SPHINGOLIPID SYNTHESIS; D-ERYTHRO-SPHINGOSINE; D-THREO-SPHINGOSINE; ASYMMETRIC PRODUCTS; AXONAL GROWTH; STEREOSELECTIVE SYNTHESIS; Neuron; Aliphatic compound; Analog; Ceramide; Sphingolipid; Amides; Aromatic compound; Chiral compound; Chemical synthesis; Biological activity; Hippocampus
• ISSN: 0022-3263; 1520-6904
• DOI: 10.1021/jo011062q

The synthesis of a new series of d-erythro-homoceramide analogues is described. Several synthetic approaches were investigated. Homoceramides can be successfully synthesized from l-homoserine as chiral building block and a protected Weinreb-amide as a key intermediate. The synthesis of short-chain analogues with a heptyl side chain, as well as with a phenyl residue in the sphingoid part (instead of the naturally occurring tridecyl side chain), was effected. The homoceramides 15−17 and 24 were investigated for their potential to reverse the inhibitory effect of fumonisin B1 on axonal growth. Unfortunately, none of the tested compounds showed any biological activity due to their lack of metabolism to glucosylhomoceramide.