Synthesis and antiviral activity of monofluoro and difluoro analogues of pyrimidine deoxyribonucleosides against human immunodeficiency virus (HIV-1).
A range of 2'-fluoro and 2',3'-difluoro analogues of pyrimidine deoxyribonucleosides have been synthesized and evaluated against human immunodeficiency virus (HIV-1) in a human lymphoblastoid cell line. Among these compounds, 1-(2,3-dideoxy-2-fluoro-beta-D-threopentofuranosyl)cytosine (12), 2',3'-didehydro-2',3'-dideoxy-2'-fluorocytidine (35), 1-(2,3-dideoxy-2,3-difluoro-beta-D-arabinofuranosyl)cytosine (41), and 3'-deoxy-2',3'-didehydro-2'-fluorothymidine (45) were found to have significant antiviral activity, with IC50 values of 0.65, 10, 10, and 100 microM, respectively. The structure-activity relationships are discussed.
Martin
J A
JA
Research Division, Roche Products Limited, Welwyn Garden City, Hertfordshire, England.
Bushnell
D J
DJ
Duncan
I B
IB
Dunsdon
S J
SJ
Hall
M J
MJ
Machin
P J
PJ
Merrett
J H
JH
Parkes
K E
KE
Roberts
N A
NA
Thomas
G J
GJ
D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D055598:Chemical Phenomena; D002621:Chemistry; D003853:Deoxyribonucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D015224:Dideoxynucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D005461:Fluorine; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D008214:Lymphocytes / Q000187:drug effects; D015394:Molecular Structure; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D016047:Zalcitabine / Q000031:analogs & derivatives / Q000138:chemical synthesis / Q000494:pharmacology
D000998:Antiviral Agents; D003853:Deoxyribonucleosides; D015224:Dideoxynucleosides; D011741:Pyrimidine Nucleosides; C065050:1-(2,3-dideoxy-2-fluoropentofuranosyl)cytosine; C065051:2',3'-dideoxy-2',3'-didehydro-2'-fluorocytidine; C065053:3'-deoxy-2',3'-didehydro-2'fluorothymidine; C065052:1-(2,3-dideoxy-2,3-difluoroarabinofuranosyl)cytosine; D005461:Fluorine; D016047:Zalcitabine