US EPA

7480435 

Book/Book Chapter 

Synthetic ceramide analogs for anticancer agents 

Ha, HJ; Lee, WK; Park, J 

2008 

Nova Science Publishers, Inc. 

Glycolipids: New Research 

145-156 

English 

Ceramide is an apoptosis-inducing signaling molecule in the sphingolipid metabolism which emerges as a potential target for anticancer therapy. Natural ceramide in solution has a uniquely folded butterfly conformer with strong internal hydrogen bonding between amide and two alcohols at C1 and C3 and with hydrophobic interaction between two long alkyl chain of sphingosine backbone and fatty acid. Its heterocyclic analogs as 3-alkanoyl or benzoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones were designed by binding of primary alcohol and amide in sphinogosine backbone as a carbamate. Those compounds without free primary alcohol have advantages not to perturb the ceramide metabolism most of which involved in the primary alcohol of sphingosine backbone. This structurally constrained analog of ceramide may have better activity compared with the natural ceramide without pre-organization of substrate, if necessary. They were synthesized by addition of acyl halide to the common ring, 4-(1-tbutyldimethylsilyloxyhexadec-2-enyl)-oxazolidin-2-one, which was elaborated from chiral aziridine-2-carboxylate including stereoselective reduction and ring opening reactions. All compounds were tested as antileukemic drugs against human leukemia HL-60 cells. Many of them including propionyl, cyclopentanoyl and p-nitrobenzoyl-4-(1-hydroxyhexadec-2-enyl)-oxazolidin-2-ones showed better antileukemic activities than natural C2-ceramide with good correlation between cell death and DNA fragmentation. Cytotoxicity was induced by caspase activation without significant accumulation of endogenous ceramide concentration or any perturbation of ceramide metabolism. © 2008 by Nova Science Publishers, Inc. All rights reserved. 

Antileukemic activity; Apoptosis; Ceramide analogs; Oxazolidin-2-one