Nucleosides and Nucleotides, Part 144 Synthesis and Antiviral Activity of 5-Substituted (2′S)-2′-Deoxy-2′-C-Methylcytidines and -uridines[1]

Synthesis of several 5‐substituted (2′S)‐2′‐deoxy‐2′‐C‐methylcytidines (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 EC50 of 0.14 μg/mL without showing cytotoxicity up to 100 μg/mL, but had a weak activity against herpes simplex virus type‐2 and no activity against varicella‐zoster virus up to 50 μg/mL in vitro. Although the 5‐fluorocytosine derivative 8b had a potent anti‐herpes simplex virus type‐1 activity (EC50 = 0.22 μg/mL), it was rather cytotoxic to the CCRF‐HSB‐2 human T‐cell line (IC50 ≥ 1.0 μg/mL).