title: 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.
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° 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.
authors.affiliation: Department of Chemistry, University of Turku, Turku, Finland. emilia.kiuru@utu.fi
authors.forename: Emilia
authors.initials: E
authors.lastname: Kiuru
authors.forename: Mikko
authors.initials: M
authors.lastname: Ora
authors.forename: Leonid
authors.initials: L
authors.lastname: Beigelman
authors.forename: Lawrence
authors.initials: L
authors.lastname: Blatt
authors.forename: Harri
authors.initials: H
authors.lastname: Lönnberg
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry*; D000818:Animals; D002236:Carbohydrate Conformation; D043182:Carboxylesterase / Q000378:metabolism; D015226:Dinucleoside Phosphates / Q000138:chemical synthesis* / Q000378:metabolism; D006863:Hydrogen-Ion Concentration; D007536:Isomerism; D009843:Oligoribonucleotides / Q000138:chemical synthesis* / Q000378:metabolism; D010710:Phosphates / Q000737:chemistry; D011355:Prodrugs / Q000138:chemical synthesis* / Q000378:metabolism; D013552:Swine
chemical_list: D015226:Dinucleoside Phosphates; D009843:Oligoribonucleotides; D010710:Phosphates; D011355:Prodrugs; D043182:Carboxylesterase; D000241:Adenosine