Synthesis and biological evaluation of 2,8-disubstituted 9-benzyladenines: Discovery of 8-mercaptoadenines as potent interferon-inducers

• Published in: Bioorganic & medicinal chemistry Vol. 11; no. 13; pp. 2715 - 2722
• Main Authors: HIROTA, Kosaku, KAZAOKA, Kazunori, SAJIKI, Hironao
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Science 03-07-2003
• Subjects: Adenine - analogs & derivatives; Adenine - chemical synthesis; Adenine - pharmacology; Animals; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - pharmacology; Biological and medical sciences; Cells, Cultured; Drug Design; Gene Expression Regulation - drug effects; Hepatitis C - drug therapy; Immunotherapy - methods; Interferons - agonists; Interferons - biosynthesis; Medical sciences; Mice; Pharmacology. Drug treatments; Spleen - cytology; Spleen - metabolism; Vesicular stomatitis Indiana virus - drug effects; Adenine derivatives; Spleen; Nitrogen heterocycle; Rodentia; Cytokine; Inducer; Splenocyte; In vitro; Vertebrata; Mammalia; Structure activity relation; Mouse; Animal; Bicyclic compound; Interferon; Chemical synthesis
• ISSN: 0968-0896; 1464-3391
• DOI: 10.1016/s0968-0896(03)00234-7

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.