title: Anti-herpesvirus activities and cytotoxicities of 2-thiopyrimidine nucleoside analogues in vitro.
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 RPM18226 (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 were 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 microM, although TN-32 was cytotoxic at a concentration of 20 microM.
authors.affiliation: Department of Microbiology, School of Medicine, Fukushima Medical University, Japan. sshigeta@cc.fmu.ac.jp
authors.forename: S
authors.initials: S
authors.lastname: Shigeta
authors.forename: S
authors.initials: S
authors.lastname: Mori
authors.forename: T
authors.initials: T
authors.lastname: Kira
authors.forename: K
authors.initials: K
authors.lastname: Takahashi
authors.forename: E
authors.initials: E
authors.lastname: Kodama
authors.forename: K
authors.initials: K
authors.lastname: Konno
authors.forename: T
authors.initials: T
authors.lastname: Nagata
authors.forename: H
authors.initials: H
authors.lastname: Kato
authors.forename: T
authors.initials: T
authors.lastname: Wakayama
authors.forename: N
authors.initials: N
authors.lastname: Koike
authors.forename: M
authors.initials: M
authors.lastname: Saneyoshi
mesh_terms: D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects* / Q000502:physiology; D006801:Humans; D009690:Nucleic Acid Conformation; D011741:Pyrimidine Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D013057:Spectrum Analysis; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides