title: Design and synthesis of novel carbocyclic versions of 2'-spirocyclopropyl ribonucleosides as potent anti-HCV agents.
abstract: The discovery of 2'-spirocyclopropyl-ribocytidine as a potent inhibitor of RNA synthesis by NS5B (IC(50) = 7.3 μM), the RNA polymerase encoded by hepatitis C virus (HCV), has led to the synthesis and biological evaluation of carbocyclic versions of 2'-spiropropyl-nucleosides from cyclopentenol 6. Spirocyclopropylation of enone 7 was completed by using (2-chloroethyl)-dimethylsulfonium iodide and potassium t-butoxide to form the desired intermediate 9a. The synthesized nucleoside analogues, 18, 19, 26, and 27, were assayed for their ability to inhibit HCV RNA replication in a subgenomic replicon Huh7 cell line. The synthesized cytosine nucleoside 19 showed moderate anti-HCV activity (IC(50) = 14.4 μM).
authors.affiliation: Biomaterials Center, Korea Institute of Science and Technology, Seoul, Republic of Korea.
authors.forename: Chang Hyun
authors.initials: CH
authors.lastname: Oh
authors.forename: Eunae
authors.initials: E
authors.lastname: Kim
authors.forename: Joon Hee
authors.initials: JH
authors.lastname: Hong
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D015195:Drug Design; D016174:Hepacivirus / Q000187:drug effects*; D006526:Hepatitis C / Q000188:drug therapy*; D006801:Humans; D012367:RNA, Viral / Q000187:drug effects; D012263:Ribonucleosides / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D013141:Spiro Compounds / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D012367:RNA, Viral; D012263:Ribonucleosides; D013141:Spiro Compounds