SYNTHESIS AND ANTIVIRAL ACTIVITY OF PRODRUGS OF THE NUCLEOSIDE 3'-C-(HYDROXYMETHYL)-BETA-D-ERYTHROPENTOFURANOSYL] CYTOSINE

Citation
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
Citations number
32
Categorie Soggetti
Biology,"Chemistry Medicinal","Chemistry Inorganic & Nuclear
ISSN journal
09680896
Volume
6
Issue
5
Year of publication
1998
Pages
577 - 585
Database
ISI
SICI code
0968-0896(1998)6:5<577:SAAAOP>2.0.ZU;2-Q
Abstract
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.