Enantiomeric Synthesis of d- and l-Cyclopentenyl Nucleosides and Their Antiviral Activity Against HIV and West Nile Virus

• Published in: Journal of medicinal chemistry 2001-11, Vol.44 (23), p.3985-3993
• Main Authors: Song, Gyu Y, Paul, Vincent, Choo, Hyunah, Morrey, John, Sidwell, Robert W, Schinazi, Raymond F, Chu, Chung K
• Format: Article
• Language: English
• Subjects: Animals; Anti-HIV Agents - chemical synthesis; Anti-HIV Agents - chemistry; Anti-HIV Agents - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Birds; Cells, Cultured; Cercopithecus aethiops; Cyclopentanes - chemical synthesis; Cyclopentanes - chemistry; Cyclopentanes - pharmacology; HIV-1 - drug effects; HIV-1 - isolation & purification; Humans; Medical sciences; Nucleosides - chemical synthesis; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology. Drug treatments; Stereoisomerism; West Nile virus - drug effects; West Nile virus - isolation & purification
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm010256v

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).