Novel Antiviral C5-Substituted Pyrimidine Acyclic Nucleoside Phosphonates Selected as Human Thymidylate Kinase Substrates

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-...

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Bibliographic Details
Published in:Journal of medicinal chemistry 2011-01, Vol.54 (1), p.222-232
Main Authors: Topalis, Dimitri, Pradère, 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
Format: Article
Language:English
Subjects:
Animal and Dairy Science
Antiviral Agents - chemical synthesis
Antiviral Agents - chemistry
Antiviral Agents - pharmacology
Catalytic Domain
Cells, Cultured
Crystallography, X-Ray
Herpesviridae - drug effects
Humans
Husdjursvetenskap
Ligands
Läkemedelskemi
Medicinal Chemistry
Models, Molecular
Molecular Structure
Nucleoside-Phosphate Kinase - antagonists & inhibitors
Nucleoside-Phosphate Kinase - metabolism
Organophosphonates - chemical synthesis
Organophosphonates - chemistry
Organophosphonates - pharmacology
Prodrugs - chemical synthesis
Prodrugs - chemistry
Prodrugs - pharmacology
Pyrimidine Nucleosides - chemical synthesis
Pyrimidine Nucleosides - chemistry
Pyrimidine Nucleosides - pharmacology
Stereoisomerism
Structure-Activity Relationship
Substrate Specificity
Thymidine - analogs & derivatives
Thymidine - chemical synthesis
Thymidine - chemistry
Thymidine - pharmacology
Thymidine Kinase - antagonists & inhibitors
Veterinary Science
Veterinärmedicin
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Description
Summary: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 cidofovir. 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 μM) and against varicella zoster virus in vitro (IC50 = 0.19 μM), 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
1520-4804
1520-4804
DOI:10.1021/jm1011462