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

The synthesis and antiviral evaluation of 21 prodrugs of 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-ery-thropentofuranosyl] 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 dicyclo-hexycarbodiimide (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. (C) 1998 Elsevier Science Ltd. All rights reserved.