title: N-substituted benzyl matrinic acid derivatives inhibit hepatitis C virus (HCV) replication through down-regulating host heat-stress cognate 70 (Hsc70) expression.
abstract: Heat-stress cognate 70 (Hsc70) is a host factor that helps hepatitis C virus (HCV) to complete its life cycle in infected hepatocytes. Using Hsc70 as a target for HCV inhibition, a series of novel N-substituted benzyl matrinic/sophoridinic acid derivatives was synthesized and evaluated for their anti-HCV activity in vitro. Among these analogues, compound 7c possessing N-p-methylbenzyl afforded an appealing ability to inhibit HCV replication with SI value over 53. Furthermore, it showed a good oral pharmacokinetic profile with area-under-curve (AUC) of 13.4 µM·h, and a considerably good safety in oral administration in mice (LD50>1000 mg/kg). As 7c suppresses HCV replication via an action mode distinctly different from that of the marketed anti-HCV drugs, it has been selected as a new mechanism anti-HCV candidate for further investigation, with an advantage of no or decreased chance to induce drug-resistant mutations.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science and Peking Union Medical College, Beijing, China.
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Chong-Wen
authors.initials: CW
authors.lastname: Bi
authors.forename: Sheng
authors.initials: S
authors.lastname: Tang
authors.forename: Ying-Hong
authors.initials: YH
authors.lastname: Li
authors.forename: Jian-Rui
authors.initials: JR
authors.lastname: Li
authors.forename: Yan-Ping
authors.initials: YP
authors.lastname: Zhu
authors.forename: Jing-Pu
authors.initials: JP
authors.lastname: Zhang
authors.forename: Yan-Xiang
authors.initials: YX
authors.lastname: Wang
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000470:Alkaloids / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D000818:Animals; D000998:Antiviral Agents / Q000009:adverse effects / Q000737:chemistry / Q000493:pharmacokinetics / Q000494:pharmacology; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects*; D050883:HSC70 Heat-Shock Proteins / Q000378:metabolism*; D016174:Hepacivirus / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008813:Mice, Inbred ICR; D011807:Quinolizines / Q000009:adverse effects / Q000737:chemistry* / Q000493:pharmacokinetics / Q000494:pharmacology*; D012449:Safety; D013329:Structure-Activity Relationship; D014779:Virus Replication / Q000187:drug effects*; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D050883:HSC70 Heat-Shock Proteins; D011807:Quinolizines; D000093842:Matrines