Structure-activity relationship of the affinity of 5-substituted uracil nucleoside analogues for varicella-zoster virus thymidine kinase and their activity against varicella-zoster virus.
We investigated structure-activity relationships of 5-substituted uracil nucleoside analogues for their selective antiviral activity against varicella-zoster virus (VZV) and affinity for VZV thymidine kinase (TK). Anti-proliferative activity of the compounds was measured using human lymphoblastoid cells. Most 2'-deoxyribofuranosyluracil, arabinofuranosyluracil (araU) and 2'-deoxy-2'-fluoro-arabinofuranosyluracil derivatives showed selective anti-VZV activity as well as activity against herpes simplex virus types 1 and 2. 2'-Deoxyuridine derivatives showed higher affinity than the corresponding araU analogues. A correlation was seen between the 50% effective doses for VZV and the Ki values for VZV TK, except for 5-ethyl-2'-deoxyuridine and 5-ethyl araU that showed relatively high affinity for VZV TK without showing any activity against VZV. 5-Halogenovinyluracil nucleosides showed the highest affinity and the most potent and selective anti-VZV activity. 2'-Deoxy-2'-fluoro-arabinofuranosyluracil derivatives exhibited high anti-VZV potency though they showed relatively low affinity for VZV TK. Some 3'-deoxythymidine analogues having anti-human immunodeficiency virus activity were inactive against herpesviruses.
Ashida
N
N
Biochemicals Division, Yamasa Corporation, Choshi, Japan.
Watanabe
Y
Y
Miura
S
S
Kano
F
F
Sakata
S
S
Yamaguchi
T
T
Suzutani
T
T
Machida
H
H
D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology; D000998:Antiviral Agents / Q000737:chemistry / Q000494:pharmacology*; D001086:Arabinofuranosyluracil / Q000737:chemistry / Q000494:pharmacology; D001087:Arabinonucleosides / Q000737:chemistry / Q000494:pharmacology; D003856:Deoxyuracil Nucleotides / Q000737:chemistry / Q000494:pharmacology*; D006131:Growth Inhibitors / Q000737:chemistry / Q000494:pharmacology; D014645:Herpesvirus 3, Human / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D006801:Humans; D054198:Precursor Cell Lymphoblastic Leukemia-Lymphoma; D013329:Structure-Activity Relationship; D013937:Thymidine Kinase / Q000037:antagonists & inhibitors / Q000737:chemistry / Q000187:drug effects*; D014407:Tumor Cells, Cultured; D014529:Uridine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology
D000970:Antineoplastic Agents; D000998:Antiviral Agents; D001087:Arabinonucleosides; D003856:Deoxyuracil Nucleotides; D006131:Growth Inhibitors; C064024:5-bromo-6-ethoxy-5,6-dihydro-2',3'-isopropylidine-beta-ribofuranosyluracil; D001086:Arabinofuranosyluracil; D013937:Thymidine Kinase; D014529:Uridine