Title: Novel antiviral C5-substituted pyrimidine acyclic nucleoside phosphonates selected as human thymidylate kinase substrates
Authors: Topalis, Dimitrios ×
Pradere, Ugo
Roy, Vincent
Caillat, Christophe
Azzouzi, Ahmed
Broggi, Julie
Snoeck, Robert
Andrei, Graciela
Lin, Jay
Eriksson, Staffan
Alexandre, Julie A. C
El-Amri, Chahrazade
Deville-Bonne, Dominique
Meyer, Philippe
Balzarini, Jan
Agrofoglio, Luigi A #
Issue Date: Jan-2011
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:54 issue:1 pages:222-232
Abstract: Acyclic nucleoside phosphonates (ANPs) are at the cornerstone of DNA virus and retrovirus therapies They reach their target, the viral DNA polymerase, after two phosphorylation steps catalyzed by cellular kinases New pyrimidine ANPs have been synthesized with unsaturated acyclic side chains (prop-2-enyl-, but-2-enyl-, pent-2-enyl-) and different substituents at the C5 position of the uracil nucleobase Several derivatives in the but-2-enyl- series 9d and 9e, with (E) but not with (Z) configuration, were efficient substrates for human thymidine monophosphate (TMP) kinase, but not for uridine monophosphate cytosine monophosphate (UMP-CMP) kinase, which is in contrast to cidofovii Human TMP kinase was successfully crystallized in a complex with phosphorylated (E)-thymidine-but-2-enyl phosphonate 9e and ADP The bis-pivaloyloxymethyl (POM) esters of (E)-9d and (E)-9e were synthesized and shown to exert activity against herpes virus in vitro (IC50 = 3 mu M) and against varicella zoster virus in vitro (IC50 = 0 19 mu M), in contrast to the corresponding inactive (Z) derivatives Thus, their antiviral activity correlates with their ability to act as thymidylate kinase substrates
ISSN: 0022-2623
Publication status: published
KU Leuven publication type: IT
Appears in Collections:Laboratory of Virology and Chemotherapy (Rega Institute)
× corresponding author
# (joint) last author

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