Structure−Activity Relationships of 2‘-Deoxy-2‘,2‘-difluoro-l-erythro-pentofuranosyl Nucleosides
journal contributionposted on 24.10.1997 by Lakshmi P. Kotra, Yuejun Xiang, M. Gary Newton, Raymond F. Schinazi, Yung-C. Cheng, Chung K. Chu
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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.