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http://dx.doi.org/10.5012/bkcs.2011.32.4.1146

2'-Spirocyclopropyl-carbocyclic Nucleoside as a Novel Scaffold for Potent Anti-HCV Agents  

Li, Hua (BK21-Project Team, College of Pharmacy, Chosun University)
Yoo, Jin-Cheol (BK21-Project Team, College of Pharmacy, Chosun University)
Hong, Joon-Hee (BK21-Project Team, College of Pharmacy, Chosun University)
Publication Information
Bulletin of the Korean Chemical Society / v.32, no.4, 2011 , pp. 1146-1152 More about this Journal
Abstract
The discovery of 2'-spirocyclopropyl-ribocytidine (J. Med. Chem. 2010, 53, 8150-8160) as a potent inhibitor of RNA synthesis by NS5B ($IC_{50}=7.3{\mu}M$), the RNA polymerase encoded by hepatitis C Virus (HCV), has led to the synthesis and biological evaluation of several carbocyclic versions of 2'-spiropropyl-nucleosides. The cyclopentenol intermediate 7 was successfully constructed via ring-closing metathesis (RCM) from divinyl 6. Spirocyclopropanation of enone 8 was effected by using (2-chloroethyl)-dimethylsulfonium iodide and potassium tert-butoxide to form the desired intermediate 9. The synthesized nucleoside analogues 21-24 were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. Among them, the cytosine nucleoside analogue 22 exhibited significant anti-HCV activity ($EC_{50}= 8.2{\mu}M$).
Keywords
Anti-HCV agent; Ring-closing metathesis; 2'-Spirocarbocyclic nucleoside;
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