STRUCTURE-ACTIVITY-RELATIONSHIPS OF 2'-DEOXY-2',2'-DIFLUORO-L-ERYTHRO-PENTOFURANOSYL NUCLEOSIDES

Following the recent discoveries that some L-nucleosides are more or e qual potent than their D-counterparts, we synthesized 2'-deoxy-2',2'-d ifluoro-L-erythro-pentofuranosyl nucleosides as potential antiviral ag ents. The target compounds were synthesized via the key intermediates 7a or 7b from L-gulono gamma-lactone. Compound 2 was oxidatively cleav ed and coupled with ethyl bromodifluoroacetate in the presence of acti vated zinc under Reformatsky conditions to obtain a diastereomeric mix ture of 4(R) and 4(S), in a 4:1 ratio. The major 4(R) isomer was cycli zed and treated appropriately to obtain the mesylate 8a or 8b, which w as condensed with various silyl-protected pyrimidines. Condensation of the alcohol 7a or 7b with 6-chloropurine under Mitsunobu conditions a fforded 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-ami no-6-chloropurine with compound 8a and subsequent treatment with 2-mer captoethanol/sodium methoxide afforded the guanine analogs 63 and 64. All of the synthesized nucleosides 31-52, 57-60, 63, and 64 were evalu ated for antiviral activity and for cellular toxicity. Adenine derivat ive 57 showed a moderate activity against HIV-1 in PBM cells (3.4 mu M ). None of the other compounds showed any significant activities again st HIV-1, HBV, HSV-1, HSV-2, and toxicity in Vero, CEM, and PBM cell l ines up to 100 mu M. The X-ray structure of the 5-iodocytosine analog showed a 2'-exo/3'-endo conformation for the carbohydrate moiety, whic h is different from those of the biologically active compounds (-)-FTC and L-FMAU.