A1 Refereed original research article in a scientific journal
Synthesis and Enzymatic Deprotection of Biodegradably Protected Dinucleoside-2 ',5 '-monophosphates: 3-(Acetyloxy)-2,2-bis(ethoxycarbonyl)propyl Phosphoesters of 3 '-O-(Acyloxymethyl)adenylyl-2 ',5 '-adenosines
Authors: Kiuru E, Ora M, Beigelman L, Blatt L, Lonnberg H
Publisher: WILEY-BLACKWELL
Publication year: 2011
Journal: Chemistry and Biodiversity
Journal name in source: CHEMISTRY & BIODIVERSITY
Journal acronym: CHEM BIODIVERS
Number in series: 2
Volume: 8
Issue: 2
First page : 266
Last page: 286
Number of pages: 21
ISSN: 1612-1872
DOI: https://doi.org/10.1002/cbdv.201000288(external)
Abstract
As a first step towards a viable prodrug strategy for short oligoribonucleotides, such as 2-5A and its congeners, adenylyl-2',5'-adenosines bearing a 3-(acetyloxy)-2,2-bis(ethoxycarbonyl)propyl group at the phosphate moiety, and an (acetyloxy)methyl-or a (pivaloyloxy)methyl-protected 3'-OH group of the 2'-linked nucleoside have been prepared. The enzyme-triggered removal of these protecting groups by hog liver carboxyesterase at pH 7.5 and 37 degrees has been studied. The (acetyloxy)methyl group turned out to be too labile for the 3'-O-protection, being removed faster than the phosphate-protecting group, which results in 2',5'- to 3',5'-isomerization of the internucleosidic phosphoester linkage. In addition, the starting material was unexpectedly converted to the 5'-O-acetylated derivative. (Pivaloyloxy)methyl group appears more appropriate for the purpose. The fully deprotected 2',5'-ApA was accumulated as a main product, although, even in this case, the isomerization of the starting material takes place.
As a first step towards a viable prodrug strategy for short oligoribonucleotides, such as 2-5A and its congeners, adenylyl-2',5'-adenosines bearing a 3-(acetyloxy)-2,2-bis(ethoxycarbonyl)propyl group at the phosphate moiety, and an (acetyloxy)methyl-or a (pivaloyloxy)methyl-protected 3'-OH group of the 2'-linked nucleoside have been prepared. The enzyme-triggered removal of these protecting groups by hog liver carboxyesterase at pH 7.5 and 37 degrees has been studied. The (acetyloxy)methyl group turned out to be too labile for the 3'-O-protection, being removed faster than the phosphate-protecting group, which results in 2',5'- to 3',5'-isomerization of the internucleosidic phosphoester linkage. In addition, the starting material was unexpectedly converted to the 5'-O-acetylated derivative. (Pivaloyloxy)methyl group appears more appropriate for the purpose. The fully deprotected 2',5'-ApA was accumulated as a main product, although, even in this case, the isomerization of the starting material takes place.
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