Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl] cytosine.

Abstract The synthesis and antiviral evaluation of 21 prodrugs of 1-[2′,3′-dideoxy-3′-C-(hydroxymethyl)-β- d -erythropentofuranosyl] cytosine 1 is reported. Cytosine N 4 -imine analogues were prepared by condensation of 1 with selected formamide dimethyl acetals. Amino acid substituted prodrugs were prepared from 1 or imine prodrug 2 by coupling with either N - tert -butoxycarbonyl ( t -Boc)- l -valine or N - t -Boc- l - phenylalanine in the presence of dicyclohexycarbodiimide (DCC) and 4-dimethylaminopyridine (4-DMAP). Deprotection of the t -Boc protecting group was achieved with trifluoroacetic acid (TFAA) in methylene chloride. Cytosine N 4 -amide analogues were prepared by reaction of 1 with appropriate anhydrides in aqueous dioxane. Triacylated analogue 22 was prepared by reaction of 1 with four equivalents of benzoyl chloride in pyridine. Prodrugs were evaluated for activity against duck hepatitis B virus, herpes simplex virus types 1 and 2, human cytomegalovirus, and human immunodeficiency virus. A number of analogues were found comparable in activity to 1 with the cytosine N 4 -imine series more active than the amino acid substituted and cytosine N 4 -amide prodrugs. Slight to moderate cellular toxicity was observed with some analogues.