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

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

* ,  and
Received: 22 November 2010 / Revised: 30 December 2010 / Accepted: 13 January 2011 / Published: 14 January 2011
(This article belongs to the collection 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
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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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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