Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus.
Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus are described. The key intermediate (-)- and (+)-cyclopentenyl alcohols (7 and 15) were prepared from D-gamma-ribonolactone and D-ribose, respectively. Coupling of 7 with appropriately blocked purine and pyrimidine bases via the Mitsunobu reaction followed by deprotection afforded the target L-(+)-cyclopentenyl nucleosides (24-28, 31, 33, and 36). D-(-)-Cyclopentenyl nucleosides (1, 40, 43, and 52-56) were also prepared by a similar procedure for L-isomers from 15. The synthesized compounds were evaluated for their antiviral activity against two RNA viruses: HIV and West Nile virus. Among the synthesized D-(-)-nucleosides, adenine (1, neplanocin A), cytosine (55, CPE-C), and 5-fluorocytosine (56) analogues exhibited moderate to potent anti-HIV activity (EC(50) 0.1, 0.06, and 5.34 microM, respectively) with significant cytotoxicity in PBM, Vero, and CEM cells. Also, cytosine (55) and 5-fluorocytosine (56) analogues exhibited the most potent anti-West Nile virus activity (EC(50) 0.2-3.0 and 15-20 microM, respectively). Among L-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC(50) 58.9 microM).
Song
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College of Pharmacy, The University of Georgia, Athens, Georgia 30602, USA.
Paul
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V
Choo
H
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Morrey
J
J
Sidwell
R W
RW
Schinazi
R F
RF
Chu
C K
CK
D000818:Animals; D019380:Anti-HIV Agents / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D001717:Birds; D002478:Cells, Cultured; D002522:Chlorocebus aethiops; D003517:Cyclopentanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects* / Q000302:isolation & purification; D006801:Humans; D009705:Nucleosides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D013237:Stereoisomerism; D014902:West Nile virus / Q000187:drug effects* / Q000302:isolation & purification
D019380:Anti-HIV Agents; D000998:Antiviral Agents; D003517:Cyclopentanes; D009705:Nucleosides