Synthesis and antiviral activity of 2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleosides, their phosphoramidate prodrugs and 5'-triphosphates.
Thirty novel α- and β-d-2'-deoxy-2'-fluoro-2'-C-methyl-7-deazapurine nucleoside analogs were synthesized and evaluated for in vitro antiviral activity. Several α- and β-7-deazapurine nucleoside analogs exhibited modest anti-HCV activity and cytotoxicity. Four synthesized 7-deazapurine nucleoside phosphoramidate prodrugs (18-21) showed no anti-HCV activity, whereas the nucleoside triphosphates (22-24) demonstrated potent inhibitory effects against both wild-type and S282T mutant HCV polymerases. Cellular pharmacology studies in Huh-7 cells revealed that the 5'-triphosphates were not formed at significant levels from either the nucleoside or the phosphoramidate prodrugs, indicating that insufficient phosphorylation was responsible for the lack of anti-HCV activity. Evaluation of anti-HIV-1 activity revealed that an unusual α-form of 7-carbomethoxyvinyl substituted nucleoside (10) had good anti-HIV-1 activity (EC(50)=0.71±0.25 μM; EC(90)=9.5±3.3 μM) with no observed cytotoxicity up to 100 μM in four different cell lines.
RFS Pharma, LLC, 1860 Montreal Road, Tucker, GA 30084, USA.
Junxing
J
Shi
Longhu
L
Zhou
Hongwang
H
Zhang
Tamara R
TR
McBrayer
Mervi A
MA
Detorio
Melissa
M
Johns
Leda
L
Bassit
Megan H
MH
Powdrill
Tony
T
Whitaker
Steven J
SJ
Coats
Matthias
M
Götte
Raymond F
RF
Schinazi
D000577:Amides / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000494:pharmacology; D002460:Cell Line; D005461:Fluorine / Q000737:chemistry; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D015394:Molecular Structure; D009705:Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology; D010756:Phosphoric Acids / Q000138:chemical synthesis / Q000494:pharmacology; D011355:Prodrugs / Q000138:chemical synthesis / Q000494:pharmacology; D011687:Purines / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
C512929:7-deazapurine; D000577:Amides; D000998:Antiviral Agents; D009705:Nucleosides; D010756:Phosphoric Acids; D011355:Prodrugs; D011687:Purines; D005461:Fluorine; C011067:phosphoramidic acid