Bulletin of the Korean Chemical Society

Korean Chemical Society (대한화학회)
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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)
  • Received : 2011.01.05
  • Accepted : 2011.01.28
  • Published : 2011.04.20
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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 ($EC_{50}= 8.2{\mu}M$).

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References

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