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-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 micrograms/mL without showing cytotoxicity up to 100 micrograms/mL, but had a weak activity against herpes simplex virus type-2 and no activity against varicella-zoster virus up to 50 micrograms/mL in vitro. Although the 5-fluorocytosine derivative 8b had a potent anti-herpes simplex virus type-1 activity (EC50 = 0.22 micrograms/mL), it was rather cytotoxic to the CCRF-HSB-2 human T-cell line (IC50 > or = 1.0 microgram/mL).
Awano
H
H
Faculty of Pharmaceutical Sciences, Hokkaido University, Sapporo, Japan.
Shuto
S
S
Miyashita
T
T
Ashida
N
N
Machida
H
H
Kira
T
T
Shigeta
S
S
Matsuda
A
A
D000818:Animals; D000970:Antineoplastic Agents / Q000138:chemical synthesis / Q000494:pharmacology; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D003841:Deoxycytidine / Q000138:chemical synthesis / Q000494:pharmacology; D003857:Deoxyuridine / Q000138:chemical synthesis / Q000494:pharmacology; D018259:Herpesvirus 1, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D013329:Structure-Activity Relationship; D014407:Tumor Cells, Cultured
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D003841:Deoxycytidine; D003857:Deoxyuridine