Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus
J Med Chem
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-γ-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 (EC50 0.1, 0.06, and 5.34 μM, 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 (EC50 0.2−3.0 and 15−20 μM, respectively). Among l-(+)-nucleosides, only the cytosine (27) analogue exhibited weak anti-HIV activity (EC50 58.9 μM).
Song, G. Y., V. Paul, H. Choo, J. Morrey, R. W. Sidwell, R. F. Schinazi, and C. K. Chu. 2001. Enantiomeric synthesis of D- and L-cyclopentenyl nucleosides and their antiviral activity against HIV and West Nile virus. J Med Chem 44:3985-3993. PMID11689085