Nucleosides. 139. Synthesis and anticytomegalovirus and antiherpes simplex virus activity of 5'-modified analogs of 2'-fluoroarabinosylpyrimidine nucleosides

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Abstract
In order to determine if modification of the 5''-position reduces or abolishes the antiviral activity of 2''-fluoro-5-iodo-ara-C (FIAC), 2''-fluoro-5-iodo-ara-U (FIAU), or 2''-fluoro-5-methyl-ara-U (FMAU) against human cytomegalovirus (HCMV) and herpes simplex virus (HSV), the 5''-deoxy,5''-mercapto, and 5''-amino analogues of these nucleosides were prepared. 5''-Deoxy-FIAC and 5''-deoxy-FIAU were prepared by catalytic hydrogenation of 5''-iodo-FIAC and 5''-iodo-FIAU to 5''-deoxy-FAC and 5''-deoxy-FAU, respectively, followed by reiodination at C-5. Reduction of 5''-iodo-FMAU afforded 5''-deoxy-FMAU. These 5''-deoxy nucleosides were found to be inactive against HCMV, indicating that the conversion to 5''-phosphate by the cellular enzyme(s) is a requirement for antiviral activity against this virus. Other 5''-modified (NH2 and SH) analogues were also prepared from 5''-O-tosyl-FIAC and 5''-O-tosy-FMAU. Treatment of these tosylates with LiN3 in DMF afforded the corresponding 5''-N3 products. Catalytic hydrogenation of 5''-N3-FMAU afforded 5''-NH2-FMAU, whereas 5''-NH2-FIAC was obtained by treatment of 5''-N3-FIAC with Ph3P in pyridine. 5''-Mercapto analogues were prepared by treatment of 5''-O-tosyl-3''-O-acetyl nucleoside with KSAc followed by deacetylation. 5''-NH2-FMAU was the only compound that showed good activity against HSV-1 and HSV-2 in vitro. However, this compound was less potent and had a lower therapeutic index than FMAU.

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