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

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journal contribution
posted on 24.10.1997, 00:00 by Lakshmi P. Kotra, Yuejun Xiang, M. Gary Newton, Raymond F. Schinazi, Yung-C. Cheng, Chung K. Chu
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 5760, 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 3152, 5760, 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.