Synthesis and antiherpesvirus activities of 5-alkyl-2-thiopyrimidine nucleoside analogues.
Twenty 5-alkyl-2-thiopyrimidine nucleosides were newly synthesized and examined for antiviral activities against herpes simplex virus (HSV), varicella-zoster virus (VZV) and human cytomegalovirus (HCMV). In this study, 2'-deoxy-5-alkyl-2-thiocytidine analogues had lower 50% effective concentration (EC50) values against HSV-1, and 2'-deoxy-5-alkyl-2-thiouridine analogues showed lower EC50 against VZV than their congeners of arabinoside form. Among the compounds examined, 2'-deoxy-5-ethyl and 5-propyl-2-thiocytidine (TN-53 and TN-54) were most potent and selective anti-HSV compounds. Their EC50s were 0.04 and 0.15 microM, and selectivity indexes were more than 7,215 and 1,849, respectively. On the other hand, 2'-deoxy-5-propyl-2-thiouridine (TN-51), 5-bromovinyl-2-thiouracil arabinoside (TN-65) and 5-styryl-2-thiouracil arabinoside (TN-67) were most potent and selective anti-VZV compounds. Their EC50s were 3.1, 3.8 and 2.6 pM for CaQu strain of VZV, respectively, and 2.1 to 3.0 times lower than that of acyclovir. All 2-thiopyrimidine nucleoside analogues did not show antiviral activities against thymidine kinase (TK) negative strains of HSV-1 and VZV. Only three 2-thiocytosine arabinoside compounds showed marginal anti-CMV activities (EC50s were 57-159 pM). All of the five alkyl-2-thio-pyrimidine nucleoside analogues examined were not cytotoxic to human lymphoblastoid cells (RPM18226) and human embryonic fibroblast cells (MRC-5) at 240 microM (100 microg/ml) or more. Regarding the structure-activity relationship of 5-alkyl-2-thiopyrimidine nucleoside analogues, the following remarks will be noted. Elongation of 5-alkyl chain (methyl to ethyl) of 2-thiocytosine in both deoxyribosyl and arabinosyl nucleosides increased anti-HSV-1 activity but not anti-VZV activity. Furthermore, elongation of the same chain (ethyl to propyl) of 2-thiodeoxyuridine increased anti-VZV activity whereas it did not in the case of 2-thiouracil arabinosides.
Shigeta
S
S
Department of Microbiology, School of Medicine, Fukushima Medical University, Japan. sshigeta@fmu.ac.jp
Mori
S
S
Watanabe
F
F
Takahashi
K
K
Nagata
T
T
Koike
N
N
Wakayama
T
T
Saneyoshi
M
M
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology / Q000633:toxicity; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects; D006564:Herpesviridae / Q000187:drug effects*; D018259:Herpesvirus 1, Human / Q000187:drug effects; D014645:Herpesvirus 3, Human / Q000187:drug effects; D006801:Humans; D011741:Pyrimidine Nucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D013329:Structure-Activity Relationship; D013872:Thionucleosides / Q000138:chemical synthesis / Q000494:pharmacology* / Q000633:toxicity; D014407:Tumor Cells, Cultured
D000998:Antiviral Agents; D011741:Pyrimidine Nucleosides; D013872:Thionucleosides