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

• Published in: Bioorganic & medicinal chemistry Vol. 6; no. 5; pp. 577 - 585
• Main Authors: Mauldin, Scott C., Paget Jr, C.J., Jones, C.David, Colacino, Joseph M., Baxter, Angela J., Staschke, Kirk A., Johansson, Nils-Gunnar, Vrang, Lotta
• Format: Journal Article
• Language: English
• Published: England Elsevier Ltd 01.05.1998
• Subjects: Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Cytomegalovirus - drug effects; Dideoxynucleosides - chemical synthesis; Dideoxynucleosides - pharmacology; Hepatitis B Virus, Duck - drug effects; HIV - drug effects; Prodrugs - chemical synthesis; Prodrugs - pharmacology; Pyrimidine Nucleosides - chemical synthesis; Pyrimidine Nucleosides - pharmacology; Spectrum Analysis; Tumor Cells, Cultured
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/S0968-0896(98)00020-0

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.