Sc. Mauldin et al., SYNTHESIS AND ANTIVIRAL ACTIVITY OF PRODRUGS OF THE NUCLEOSIDE 3'-C-(HYDROXYMETHYL)-BETA-D-ERYTHROPENTOFURANOSYL] CYTOSINE, Bioorganic & medicinal chemistry, 6(5), 1998, pp. 577-585
The synthesis and antiviral evaluation of 21 prodrugs of '-C-(hydroxym
ethyl)-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 prepa
red from 1 or imine prodrug 2 by coupling with either N-tert-butoxycar
bonyl (t-Boc)-L-valine or N-t-Boc-L- phenylalanine in the presence of
dicyclo-hexycarbodiimide (DCC) and 4-dimethylaminopyridine (4-DMAP). D
eprotection of the t-Boc protecting group was achieved with trifluoroa
cetic 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 fo
ur equivalents of benzoyl chloride in pyridine. Prodrugs were evaluate
d for activity against duck hepatitis B virus, herpes simplex virus ty
pes 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 r
ights reserved.