title: A novel class of geldanamycin derivatives as HCV replication inhibitors targeting on Hsp90: synthesis, structure-activity relationships and anti-HCV activity in GS4.3 replicon cells.
abstract: A novel class of geldanamycin (GA) derivatives as hepatitis C virus (HCV) replication inhibitors has been synthesized and their anti-HCV activities were evaluated in GS4.3 HCV replicon cells. Most of the synthesized compounds demonstrated potential activities against HCV in vitro. Substitution with an aliphatic cyclic group (2b) and polar phosphate group (2f) at the 17 position of GA resulted in more potent inhibitory activity. The configurations of the tetrahydrofurfurylamino (THFM) substituents obviously affected their antiviral activities. The 2b with a 2'-(R)-THFM group at the 17 position showed much potent activity and higher selectivity than its 2'-(S) and 2'-(R, S) epimers. In the tested GA derivatives, 2b and 2f show the most potential leading compounds for development of novel anti-HCV agents.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, PR China.
authors.forename: Guang-zhi
authors.initials: GZ
authors.lastname: Shan
authors.forename: Zong-gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Yu-huan
authors.initials: YH
authors.lastname: Li
authors.forename: Dong
authors.initials: D
authors.lastname: Li
authors.forename: Yan-ping
authors.initials: YP
authors.lastname: Li
authors.forename: Shuai
authors.initials: S
authors.lastname: Meng
authors.forename: Lin-yan
authors.initials: LY
authors.lastname: Gao
authors.forename: Jian-dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Zhuo-rong
authors.initials: ZR
authors.lastname: Li
mesh_terms: D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D016227:Benzoquinones / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D016174:Hepacivirus / Q000187:drug effects*; D006801:Humans; D020128:Inhibitory Concentration 50; D047029:Lactams, Macrocyclic / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology* / Q000633:toxicity; D008826:Microbial Sensitivity Tests; D013329:Structure-Activity Relationship; D013778:Tetrazolium Salts / Q000378:metabolism; D013844:Thiazoles / Q000378:metabolism; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000998:Antiviral Agents; D016227:Benzoquinones; D047029:Lactams, Macrocyclic; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue; C001277:geldanamycin