Nucleosides and nucleotides .144. Synthesis and antiviral activity of 5-substituted (2'S)-2'-deoxy-2'-C-methylcytidines and -uridines

Synthesis of several 5-substituted (2'S)-2'-deoxy-2'-C-methyl-cytidines (8) and -uridines (6,11) has been accomplished using radical deoxygenation of the 2'-tert-alcohols via their methyl oxalyl esters as a key reaction. Anti-herpes simplex virus type-1 and -2, and anti-varicella-zoster virus activities of the newly synthesized nucleosides were evaluated. Among them, the 5-iodouracil derivative 6e showed the most potent activity against herpes simplex virus type-1, with an EC(50) of 0.14 mu g/mL without showing cytotoxicity up to 100 mu g/mL, but had a weak activity against herpes simplex virus type-2 and no activity against varicella-zoster virus up to 50 mu g/mL in vitro. Although the 5-fluorocytosine derivative 8b had a potent anti-herpes simplex virus type-1 activity (EC(50) = 0.22 mu g/mL), it was rather cytotoxic to the CCRF-HSB-2 human T-cell line (IC50 greater than or equal to 1.0 mu g/mL).