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

Molecules

Mikko Ora¹  Anne Mäntyvaara¹ 

[1] Department of Chemistry, University of Turku, FIN-20014 Turku, Finland

关键词: prodrug;    nucleotide;    biodegradable;    protecting group;   

DOI  :  10.3390/molecules16010552

来源: mdpi

【 摘 要 】

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).

【 授权许可】

CC BY   
This is an open access article distributed under the Creative Commons Attribution License (CC BY) which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.