Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: discovery of 8-mercaptoadenines as potent interferon-inducers.
Recently, we have identified 9-benzyl-8-hydroxyadenines bearing an appropriate substituent (a butoxy, propylthio or butylamino group) at the 2-position as potent interferon (IFN)-inducers. Herein we report the design, synthesis, and IFN-inducing activity of 8-substituted 9-benzyladenines possessing such an appropriate substituent at the 2-position. Introduction of the appropriate substituent into the 2-position of the adenine nucleus gave rise to expression of the activity even in 9-benzyladenines bearing no hydroxyl group at the 8-position. An amino group at the 6-position and a hydroxyl or thiol group carrying an acidic proton at the 8-position are required to express excellent IFN-inducing activity. 9-Benzyl-2-butoxy-8-mercaptoadenine (9) indicated the most potent activity with MEC of 0.001 microM.
Hirota
Kosaku
K
Laboratory of Medicinal Chemistry, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan. hirota@gifu-pu.ac.jp
Kazaoka
Kazunori
K
Sajiki
Hironao
H
D000225:Adenine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000494:pharmacology; D002478:Cells, Cultured; D015195:Drug Design; D005786:Gene Expression Regulation / Q000187:drug effects; D006526:Hepatitis C / Q000188:drug therapy; D007167:Immunotherapy / Q000379:methods; D007372:Interferons / Q000819:agonists* / Q000096:biosynthesis; D051379:Mice; D013154:Spleen / Q000166:cytology / Q000378:metabolism; D014721:Vesicular stomatitis Indiana virus / Q000187:drug effects
D000998:Antiviral Agents; C055872:9-benzyladenine; C001700:meradine; D007372:Interferons; D000225:Adenine