3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl groups as biodegradable protecting groups of nucleoside 5´-mono-phosphates.
Thymidine 5´-bis[3-acetyloxy-2-cyano-2-(2-phenylethylcarbamoyl)propyl]phosphate (1) has been prepared and the removal of phosphate protecting groups by hog liver carboxyesterase (HLE) at pH 7.5 and 37 °C has been followed by HPLC. The first detectable intermediates are the (R(P))- and (S(P))-diastereomers of the monodeacetylated triester 14, which subsequently undergo concurrent retro-aldol condensation to diester 4 and enzyme-catalyzed hydrolysis to the fully deacetylated triester 15. The former pathway predominates, representing 90% of the overall breakdown of 14. The diester 4 undergoes the enzymatic deacetylation 700 times less readily than the triester, but gives finally thymidine 5´-monophosphate as the desired main product. To elucidate the potential toxicity of the electrophilic 2-cyano-N-(2-phenylethyl)acrylamideby-product 17 released upon the deprotection, the hydrolysis of 1 has also been studied in the presence of glutathione (GSH).
Department of Chemistry, University of Turku, FIN-20014 Turku, Finland. mikora@utu.fi
Mikko
M
Ora
Anne
A
Mäntyvaara
Harri
H
Lönnberg
D000107:Acetylation; D002384:Catalysis; D002851:Chromatography, High Pressure Liquid; D003486:Cyanides / Q000737:chemistry*; D005978:Glutathione / Q000737:chemistry; D006207:Half-Life; D006868:Hydrolysis; D013058:Mass Spectrometry; D009705:Nucleosides / Q000737:chemistry*
D003486:Cyanides; D009705:Nucleosides; D005978:Glutathione
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