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

被引:3
|
作者
Ora, Mikko [1 ]
Mantyvaara, Anne [1 ]
Lonnberg, Harri [1 ]
机构
[1] Univ Turku, Dept Chem, FIN-20014 Turku, Finland
关键词
prodrug; nucleotide; biodegradable; protecting group; ANTI-HIV ACTIVITY; IN-VITRO; 3-(PIVALOYLOXY)PROPYL GROUPS; ORAL BIOAVAILABILITY; NUCLEOTIDE PRODRUGS; OLIGONUCLEOTIDES; BIOACTIVATION; PHOSPHATES; DELIVERY; SATE;
D O I
10.3390/molecules16010552
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
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 degrees 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).
引用
收藏
页码:552 / 566
页数:15
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