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Nucleoside Mono‐ and Diphosphate Prodrugs of 2′,3′‐Dideoxyuridine and 2′,3′‐Dideoxy‐2′,3′‐didehydrouridine
Author(s) -
Pertenbreiter Florian,
Balzarini Jan,
Meier Chris
Publication year - 2015
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402295
Subject(s) - prodrug , nucleotide , nucleoside , nucleoside diphosphate kinase , chemistry , intracellular , biochemistry , nucleoside triphosphate , stereochemistry , enzyme , gene
Despite their close structural similarity to nucleoside analogues such as the anti‐HIV drugs AZT and d4T, 2′,3′‐dideoxyuridine (ddU) and 2′,3′‐dideoxy‐2′,3′‐didehydrouridine (d4U) are entirely inactive against HIV in their nucleoside form. However, it has been shown that the corresponding triphosphates of these two nucleosides can effectively block HIV reverse transcriptase. Herein we report on two types of nucleotide prodrugs ( cyclo Sal and Di PP ro nucleotides) of ddU and d4U to investigate their ability to overcome insufficient intracellular phosphorylation, which may be the reason behind their low anti‐HIV activity. The release of the corresponding mono‐ and diphosphates from these compounds was demonstrated by hydrolysis studies in phosphate buffer (pH 7.3) and human CD 4 + T‐lymphocyte CEM cell extracts. Surprisingly, however, these compounds showed low or no anti‐HIV activity in tests with human CD 4 + T‐lymphocyte CEM cells. Studies of the conversion of ddUDP and d4UDP into their triphosphate metabolites by nucleoside diphosphate kinase (NDPK) showed nearly no conversion of either diphosphate, which may be the reason for low intracellular triphosphate levels that result in low antiviral activity.