Synthesis and growth inhibitory activity of chiral 5-hydroxy-2-N-acyl-(3E)-sphingenines: ceramides with an unusual sphingoid backbone.
The unusual sphingoid base 5-hydroxy-3-sphingenine was identified in the hydrolysate of brain sphingolipids more than 40 years ago. We present here the first synthesis of the 5R and 5S diastereoisomers of the N-acyl derivatives of 5-hydroxy-3-sphingenine, 2 and 3, respectively, which represent regioisomers of (2S,3R)-ceramide (1). The key steps include the synthesis of alpha,beta-unsaturated ketone intermediates 4 and 5 from N-Cbz- and N-Boc-l-serine and diastereoselective reduction of the enones. The configuration at the new carbinol center was deduced by proton NMR analysis of (R)- and (S)-Mosher [methoxy(trifluoromethyl)phenylacetate] ester derivatives. Ceramide analogues 2 and 3 showed a markedly higher antiproliferative activity than 1 on MCF-7 cells.
Chun
Jiong
J
Department of Chemistry and Biochemistry, Queens College of The City University of New York, Flushing 11367-1597, USA.
Byun
Hoe-Sup
HS
Arthur
Gilbert
G
Bittman
Robert
R
D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D001923:Brain Chemistry; D001943:Breast Neoplasms; D002384:Catalysis; D002518:Ceramides / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D002625:Chemistry, Organic / Q000379:methods*; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D009682:Magnetic Resonance Spectroscopy; D015394:Molecular Structure; D012694:Serine / Q000737:chemistry; D013110:Sphingosine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014407:Tumor Cells, Cultured / Q000187:drug effects
D000970:Antineoplastic Agents; D002518:Ceramides; D012694:Serine; D013110:Sphingosine