Ester Prodrugs of Cyclic 1-(S)-[3-Hydroxy-2-(phosphonomethoxy)propyl]-5-azacytosine:Synthesis and Antiviral Activity

摘要

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 hexadecyloxy ethyl ester 5.The relative configuration of the diastereoisomer trans-6 was determined using H,H-NOESY NMR.