Title: Ester prodrugs of cyclic 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine: synthesis and antiviral activity
Authors: Krecmerová, Marcela ×
Holý, Antonín
Pohl, Radek
Masojídková, Milena
Andrei, Graciela
Naesens, Lieve
Neyts, Johan
Balzarini, Jan
De Clercq, Erik
Snoeck, Robert #
Issue Date: 13-Nov-2007
Publisher: ACS Publications
Series Title: Journal of Medicinal Chemistry vol:50 issue:23 pages:5765-5772
Abstract: Reaction of 1-(S)-[3-hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine (1) with dicyclohexylcarbodiimide and N,N,-dicyclohexyl-4-morpholinocarboxamidine in dimethylformamide at elevated temperature afforded the corresponding cyclic phosphonate 2, that is, 1-{[(5S)-2-hydroxy-2-oxido-1,4,2-dioxaphosphinan-5-yl]methyl}-5-azacytosine. Compound 2 exerts strong in vitro activity against DNA viruses, comparable with activity of parent compound 1. Transformation of 2 to its tetrabutylammonium salt followed by reaction with alkyl or acyloxyalkyl halogenides enabled us to prepare a series of structurally diverse ester prodrugs: alkyl (octadecyl), alkenyl (erucyl), alkoxyalkyl (hexadecyloxyethyl), and acyloxyalkyl (pivaloyloxymethyl) (3-6). The introduction of an alkyl, alkoxyalkyl, or acyloxyalkyl ester group to the molecule resulted in an increase of antiviral activity; the most active compound was found to be the hexadecyloxyethyl ester 5. The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.
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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