Structure−Activity Relationships of 2‘-Deoxy-2‘,2‘-difluoro-l-erythro-pentofuranosyl Nucleosides

• Published in: Journal of medicinal chemistry Vol. 40; no. 22; pp. 3635 - 3644
• Main Authors: Kotra, Lakshmi P, Xiang, Yuejun, Newton, M. Gary, Schinazi, Raymond F, Cheng, Yung-C, Chu, Chung K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 24.10.1997; Amer Chemical Soc
• Subjects: Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Chemistry, Medicinal; Hepatitis B virus - drug effects; Herpesvirus 1, Human - drug effects; Herpesvirus 2, Human - drug effects; HIV-1 - drug effects; Life Sciences & Biomedicine; Medical sciences; Nucleosides - chemistry; Nucleosides - pharmacology; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Spectrum Analysis; Structure-Activity Relationship; ASYMMETRIC-SYNTHESIS; POTENTIAL ANTIVIRAL AGENTS; METABOLISM; ANALOGS; PYRIMIDINE; BIOLOGICAL EVALUATION; RESISTANCE; HEPATITIS-B VIRUS; ANTI-HIV AGENTS; HUMAN-IMMUNODEFICIENCY-VIRUS; Purine nucleoside; HIV-1 virus; Retroviridae; Lentivirus; In vitro; Virus; Structure activity relation; L stereoisomer; Antiviral; Fluorine Organic compounds; Human immunodeficiency virus; Chemical synthesis; Pyrimidine nucleoside
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm970275y

Following the recent discoveries that some l-nucleosides are more or equal potent than their d-counterparts, we synthesized 2‘-deoxy-2‘,2‘-difluoro-l-erythro-pentofuranosyl nucleosides as potential antiviral agents. The target compounds were synthesized via the key intermediates 7a or 7b from l-gulono γ-lactone. Compound 2 was oxidatively cleaved and coupled with ethyl bromodifluoroacetate in the presence of activated zinc under Reformatsky conditions to obtain a diastereomeric mixture of 4(R) and 4(S), in a 4:1 ratio. The major 4(R) isomer was cyclized and treated appropriately to obtain the mesylate 8a or 8b, which was condensed with various silyl-protected pyrimidines. Condensation of the alcohol 7a or 7b with 6-chloropurine under Mitsunobu conditions afforded the 6-chloropurine analogs 53a or 53b and 54a or 54b. Further treatment of the compounds 53a, 54a and 53b, 54b afforded the inosine and adenine derivatives 57−60, respectively. The condensation of 2-amino-6-chloropurine with compound 8a and subsequent treatment with 2-mercaptoethanol/sodium methoxide afforded the guanine analogs 63 and 64. All of the synthesized nucleosides 31−52, 57−60, 63, and 64 were evaluated for antiviral activity and for cellular toxicity. Adenine derivative 57 showed a moderate activity against HIV-1 in PBM cells (3.4 μM). None of the other compounds showed any significant activities against HIV-1, HBV, HSV-1, HSV-2, and toxicity in Vero, CEM, and PBM cell lines up to 100 μM. The X-ray structure of the 5-iodocytosine analog showed a 2‘-exo/3‘-endo conformation for the carbohydrate moiety, which is different from those of the biologically active compounds (−)-FTC and l-FMAU.