Synthesis and Anti-Hepatitis B Virus and Anti-Hepatitis C Virus Activities of 7-Deazaneplanocin A Analogues in Vitro

• Published in: Journal of medicinal chemistry Vol. 52; no. 1; pp. 206 - 213
• Main Authors: Kim, Hyo-Joong, Sharon, Ashoke, Bal, Chandralata, Wang, Jianing, Allu, Madhan, Huang, Zhuhui, Murray, Michael G, Bassit, Leda, Schinazi, Raymond F, Korba, Brent, Chu, Chung K
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 08.01.2009; Amer Chemical Soc
• Subjects: Adenosine - analogs & derivatives; Adenosine - chemical synthesis; Adenosine - chemistry; Adenosine - pharmacology; Antibiotics. Antiinfectious agents. Antiparasitic agents; Antiviral agents; Antiviral Agents - chemical synthesis; Antiviral Agents - chemistry; Antiviral Agents - pharmacology; Biological and medical sciences; Cell Line, Tumor; Cell Survival - drug effects; Chemistry, Medicinal; Hepacivirus - drug effects; Hepacivirus - physiology; Hepatitis B virus - drug effects; Hepatitis B virus - genetics; Humans; Life Sciences & Biomedicine; Medical sciences; Molecular Structure; Mutation - genetics; Pharmacology & Pharmacy; Pharmacology. Drug treatments; Science & Technology; Virus Replication - drug effects; NEPLANOCIN-A; POTENT INHIBITOR; REPLICATION; MECHANISM; ANTIVIRAL ACTIVITY; CYCLOPENTENYL NUCLEOSIDES; 3-DEAZANEPLANOCIN-A; S-ADENOSYLHOMOCYSTEINE HYDROLASE; RNA-POLYMERASE; COWPOX VIRUS; Nitrogen heterocycle; Orthohepadnavirus; Deazanucleoside; In vitro; Virus; Cyclitol; Structure activity relation; Hepadnaviridae; Bicyclic compound; Antiviral; Hepatitis B virus; Flaviviridae; Chemical synthesis; Hepatitis C virus; Hepacivirus; Ethylenic compound
• ISSN: 0022-2623; 1520-4804
• DOI: 10.1021/jm801418v

A series of 7-deazaneplanocin A (7-DNPA, 2) analogues were synthesized and evaluated for in vitro antiviral activity against HBV and HCV. The syntheses of target carbocyclic nucleosides were accomplished via a convergent procedure. 7-Substitutions were introduced by using 7-substituted-7-deaza heterocyclic base precursors (F, Cl, Br, and I) or via substitution reactions after the synthesis of the carbocyclic nucleosides. Among the synthesized compounds, 2, 13−15, 24, and 27 exhibited significant anti-HCV activity (EC50 ranged from 1.8 to 20.1 μM) and compounds 2, 15, 22, and 24 demonstrated moderate to potent anti-HBV activity (EC50 = 0.3−3.3 μM). In addition, compound 24 also showed activity against lamivudine- and adefovir-associated HBV mutants.