Synthesis and antiviral evaluation of certain novel pyrazinoic acid C-nucleosides.
Pyrazine (1,4-diazine) C-nucleosides constitute a rare class of nucleic acid analogues that has only recently been reported in the literature. As part of our ongoing investigation into the synthesis and reactivity of these compounds, we have developed an electrophilic esterification of a lithiated pyrazine C-nucleoside (1) to give, following deprotection, the versatile intermediate ethyl 3,5-dichloro-6-(beta-d-ribofuranosyl)pyrazine-2-carboxylate (4). This intermediate was subjected to a variety of reaction conditions to generate a series of pyrazinoic acid C-nucleosides. These compounds, along with 3, 5-dichloro-2-(beta-d-ribofuranosyl)pyrazine (2) and 4, were evaluated for antiviral activity and cytotoxicity. No significant activity was observed for compounds 2 and 5-9, but 4 was active against two herpes viruses and cytotoxic in the micromolar range.
Walker
J A
JA
Department of Medicinal Chemistry, College of Pharmacy, University of Michigan, Ann Arbor, Michigan 48109-1065, USA.
Liu
W
W
Wise
D S
DS
Drach
J C
JC
Townsend
L B
LB
D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology*; D002455:Cell Division / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003587:Cytomegalovirus / Q000187:drug effects / Q000254:growth & development; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D004797:Enzyme-Linked Immunosorbent Assay; D005347:Fibroblasts / Q000187:drug effects / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000254:growth & development; D006801:Humans; D007624:KB Cells; D008826:Microbial Sensitivity Tests; D011719:Pyrazines / Q000138:chemical synthesis* / Q000494:pharmacology*; D012266:Ribose / Q000138:chemical synthesis* / Q000494:pharmacology*; D012867:Skin / Q000166:cytology / Q000187:drug effects / Q000821:virology; D010948:Viral Plaque Assay
D000998:Antiviral Agents; D011719:Pyrazines; C111639:ethyl 3,5-dichloro-6-(ribofuranosyl)pyrazine-2-carboxylate; D012266:Ribose