Synthesis and antiviral activity of 3'-C-cyano-3'-deoxynucleosides.

A series of 3'-C-cyano-3'-deoxynucleosides have been synthesized and evaluated as antiviral agents. Reaction of 2',5'-bis-O-(tert-butyldimethylsilyl)-beta-D-erythro-pentofuranos- 3'-ulosyl derivatives of uracil, 4-N-acetylcytosine, and adenine with sodium cyanide gave a mixture of epimeric cyanohydrins, which after 3'-deoxygenation yielded the corresponding 3'-C-cyano-3'-deoxy-beta-D-xylo-pentofuranosyl derivatives 10. These compounds were epimerized to the corresponding beta-D-ribo-pentofuranosyl derivatives 11. Desilylation of 10 and 11 gave the deprotected 3'-C-cyano-3'-deoxy-beta-D-xylo- and -ribo-pentofuranosyl nucleosides. These derivatives of uridine, cytidine, and adenine, as well as the 3'-C-cyano-3'-deoxy-beta-D-xylo- and -ribo-pentofuranosyl, 3'-C-cyano-2',3'-dideoxy-beta-D-threo- and -erythro-pentofuranosyl, and 3'-C-cyano-2',3'-dideoxy-beta-D-glycero-pent-2'-enofuranosyl derivatives of thymine, were evaluated for their antiviral activity. None of the compounds proved active against the replication of retroviruses (human immunodeficiency virus, murine sarcoma virus) at concentrations that were not toxic to the host cells. However, the 3'-C-cyano-3'-deoxy-beta-D-xylo- (12e) and -ribo-pentofuranosyl (13e) derivatives of adenine showed activity against some DNA (i.e., vaccinia) and RNA (i.e., Sindbis, Semliki forest) viruses at concentrations well below the cytotoxicity threshold.