Synthesis of sphingomyelin carbon analogues as sphingomyelinase inhibitors.
The highly efficient and stereocontrolled syntheses of sphingomyelin carbon analogues 1 and 2 were achieved by effectively utilizing Hofmann rearrangement of enantiomerically pure beta-hydroxyamide 7, which was prepared by an asymmetric hydrogenation of alpha-acyl-gamma-butyrolactone 9 and ring opening with NH(3). Intermediary isocyanate 6 was selectively trapped with the vicinal hydroxy group in an intramolecular fashion to produce an oxazolidinone derivative, 5. In the synthesis of a quite polar compound such as 1, a convenient one-pot procedure of the introduction of a benzyloxycarbonyl group into the hydroxy group resulting from the oxazolidinone ring opening is another key point, because, in addition to the efficiency, this protecting group was easily removable by a simple procedure and workup at the final step. Both synthesized compounds 1 and 2 showed moderate inhibitory activity toward sphingomyelinase from B. cereus.
Hakogi
Toshikazu
T
School of Science, Kwansei Gakuin University, Gakuen, Sanda, Hyogo 669-1337, Japan.
Monden
Yoshiko
Y
Taichi
Misako
M
Iwama
Seiji
S
Fujii
Shinobu
S
Ikeda
Kiyoshi
K
Katsumura
Shigeo
S
D017209:Apoptosis; D001409:Bacillus cereus / Q000201:enzymology; D002625:Chemistry, Organic / Q000379:methods; D002851:Chromatography, High Pressure Liquid; D003500:Cyclization; D004305:Dose-Response Relationship, Drug; D004791:Enzyme Inhibitors / Q000138:chemical synthesis*; D007202:Indicators and Reagents; D015394:Molecular Structure; D017550:Spectroscopy, Fourier Transform Infrared; D013108:Sphingomyelin Phosphodiesterase / Q000037:antagonists & inhibitors* / Q000737:chemistry; D013109:Sphingomyelins / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D013237:Stereoisomerism
D004791:Enzyme Inhibitors; D007202:Indicators and Reagents; D013109:Sphingomyelins; D013108:Sphingomyelin Phosphodiesterase