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-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 (IC(50) = 3 μM) and against varicella zoster virus in vitro (IC(50) = 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.
Groupe d'Enzymologie Moléculaire et Fonctionnelle, UR4-UPMC, Université Pierre et Marie Curie, Sorbonne Universités, Paris, France.
Dimitri
D
Topalis
Ugo
U
Pradère
Vincent
V
Roy
Christophe
C
Caillat
Ahmed
A
Azzouzi
Julie
J
Broggi
Robert
R
Snoeck
Graciela
G
Andrei
Jay
J
Lin
Staffan
S
Eriksson
Julie A C
JA
Alexandre
Chahrazade
C
El-Amri
Dominique
D
Deville-Bonne
Philippe
P
Meyer
Jan
J
Balzarini
Luigi A
LA
Agrofoglio
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D020134:Catalytic Domain; D002478:Cells, Cultured; D018360:Crystallography, X-Ray; D006564:Herpesviridae / Q000187:drug effects; D006801:Humans; D008024:Ligands; D008958:Models, Molecular; D015394:Molecular Structure; D009703:Nucleoside-Phosphate Kinase / Q000037:antagonists & inhibitors / Q000378:metabolism*; D063065:Organophosphonates / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013379:Substrate Specificity; D013936:Thymidine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors
D000998:Antiviral Agents; D008024:Ligands; C562241:N1-(4-bis(pivaloyloxymethyl)phosphinylbuten-2-yl)thymine; D063065:Organophosphonates; D011355:Prodrugs; D011741:Pyrimidine Nucleosides; C105339:thymidine kinase 2; D013937:Thymidine Kinase; C092717:thymidine kinase 1; C019979:cytidylate kinase; D009703:Nucleoside-Phosphate Kinase; C020093:dTMP kinase; D013936:Thymidine