Synthesis and antiviral activity of prodrugs of the nucleoside 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl] cytosine.
The synthesis and antiviral evaluation of 21 prodrugs of 1-[2',3'-dideoxy-3'-C-(hydroxymethyl)-beta-D-erythropentofuranosyl ] cytosine 1 is reported. Cytosine N4-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 N4-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 N4-imine series more active than the amino acid substituted and cytosine N4-amide prodrugs. Slight to moderate cellular toxicity was observed with some analogues.
Mauldin
S C
SC
Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, IN 46285, USA.
Paget
C J
CJ
Jones
C D
CD
Colacino
J M
JM
Baxter
A J
AJ
Staschke
K A
KA
Johansson
N G
NG
Vrang
L
L
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003587:Cytomegalovirus / Q000187:drug effects; D015224:Dideoxynucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D006678:HIV / Q000187:drug effects; D015611:Hepatitis B Virus, Duck / Q000187:drug effects; D011355:Prodrugs / Q000138:chemical synthesis* / Q000494:pharmacology; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis* / Q000494:pharmacology; D013057:Spectrum Analysis; D014407:Tumor Cells, Cultured
C113790:1-(2',3'-dideoxy-3'(hydroxymethyl)erythropentofuranosyl)cytosine; D000998:Antiviral Agents; D015224:Dideoxynucleosides; D011355:Prodrugs; D011741:Pyrimidine Nucleosides