Anti-herpesvirus activities and cytotoxicities of 2-thiopyrimidine nucleoside analogues in vitro

S. Shigeta, S. Mori, T. Kira, K. Takahashi, E. Kodama, K. Konno, T. Nagata, H. Kato, T. Wakayama, N. Koike, M. Saneyoshi

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30 Citations (Scopus)

Abstract

Twenty 2-thiopyrimidine nucleoside analogues were synthesized and examined for inhibitory activity against herpes simplex virus (HSV) type 1 and 2, varicella-zoster virus (VZV), human cytomegalovirus (HCMV) and thymidine kinase-deficient HSV (HSV-TK-) replication in vitro. 2-thiouracil (thymine) arabinoside, 2'-deoxy-2-thiouridine (or 2-thiothymidine) and their 5-halogenated derivatives showed anti-HSV activity in both RPMI8226 (human B-lymphoblastoid cells) and MRC-5 (human embryo lung cells). 2'-deoxy-5-halogenated-2-thiocytidines were also inhibitory against HSV, whereas 2-thiocytosine arabinoside and its derivatives were not inhibitory against HSV replication, except 5-bromo and 5-iodo congeners (TN-31, TN-32). Substitution of the halogen atom at the 5-position of the pyrimidine rings to an atom with a higher molecular weight increased anti-HSV and VZV activities, except for the anti-HSV activity of 2-thiouracil arabinosides. 2'-deoxy-5-methyl-, and 2'-deoxy-5-iodo-2-thiouridines (TN-17, TN-44) showed the most potent anti-HSV activity, and 2'-deoxy-5-chloro and 2'-deoxy-5-bromo-2-thiocytidines potent inhibitors of VZV replication. However, none of the compounds inhibited HCMV and HSV-TK- replication. TN-31 and TN-32 were shown to inhibited HCMV and HSV-TK- as well as HSV and VZV replication. The cytotoxicity of the 2-thio-pyrimidine nucleoside analogues was less than that of the 2-oxy-congeners of the compounds (5-iodo-2'-deoxyuridine, 5-iodo-2'-deoxycytidine, thymine arabinoside and cytosine arabinoside). The selectivity index of 2'-deoxy-5-iodo-2-thiouridine (TN-44) was higher than that of 5-iodo-deoxyuridine. TN-17 and TN-44 were not cytotoxic to resting or stimulated human peripheral blood mononuclear cells at 400 μM, although TN-32 was cytotoxic at a concentration of 20 μM.

Original languageEnglish
Pages (from-to)195-209
Number of pages15
JournalAntiviral Chemistry and Chemotherapy
Volume10
Issue number4
DOIs
Publication statusPublished - 1999 Jul

Keywords

  • 2-Thiopyrimidine nucleoside
  • Cytotoxicity
  • Herpes simplex virus
  • Human cytomegalovirus
  • Varicella-zoster virus

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