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Molecules 2011, 16(1), 552-566; doi:10.3390/molecules16010552

3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl Groups as Biodegradable Protecting Groups of Nucleoside 5´-mono-Phosphates

Department of Chemistry, University of Turku, FIN-20014 Turku, Finland
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Received: 22 November 2010 / Revised: 30 December 2010 / Accepted: 13 January 2011 / Published: 14 January 2011
(This article belongs to the Special Issue Prodrugs)
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Abstract

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 (RP)- and (SP)-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).
Keywords: prodrug; nucleotide; biodegradable; protecting group prodrug; nucleotide; biodegradable; protecting group
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Ora, M.; Mäntyvaara, A.; Lönnberg, H. 3-Acetyloxy-2-cyano-2-(alkylaminocarbamoyl)propyl Groups as Biodegradable Protecting Groups of Nucleoside 5´-mono-Phosphates. Molecules 2011, 16, 552-566.

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