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.
- MeSH
- antivirové látky farmakologie chemická syntéza chemie MeSH
- buněčné linie MeSH
- cytosin analogy a deriváty farmakologie chemie MeSH
- DNA viry účinky léků MeSH
- estery MeSH
- financování organizované MeSH
- isomerie MeSH
- lidé MeSH
- magnetická rezonanční spektroskopie MeSH
- prekurzory léčiv farmakologie chemická syntéza chemie MeSH
- Retroviridae účinky léků MeSH
- RNA-viry účinky léků MeSH
- virová léková rezistence MeSH
- vztahy mezi strukturou a aktivitou MeSH
- Check Tag
- lidé MeSH
- MeSH
- antivirové látky farmakologie chemicky indukované chemie MeSH
- Cytomegalovirus účinky léků MeSH
- kyseliny fosforu farmakologie chemicky indukované chemie MeSH
- lidé MeSH
- myši MeSH
- purinové nukleotidy farmakologie chemicky indukované chemie MeSH
- pyrimidinové nukleotidy farmakologie chemicky indukované chemie MeSH
- virus vakcinie účinky léků MeSH
- zvířata MeSH
- Check Tag
- lidé MeSH
- myši MeSH
- zvířata MeSH
