title: Design and synthesis of oxymatrine analogues overcoming drug resistance in hepatitis B virus through targeting host heat stress cognate 70.
abstract: Heat-stress cognate 70 (Hsc70) is a host protein required for hepatitis B virus (HBV) replication, and oxymatrine (1) suppresses Hsc70 expression. Taking Hsc70 as a target against HBV, 22 analogues of 1 defined with substituents at position 1, 13, or 14 were synthesized and evaluated for their activity on Hsc70 mRNA expression. The SAR revealed that (i) the oxygen atom at the 1-position was not essential, (ii) increasing electron density on the ring D reduced the activity, and (iii) introducing a proper substituent at the 13- and/or 14-position(s), especially electron-withdrawing groups, might enhance the activity. Among the analogues, 6b possessing 13-ethoxyl afforded an increased activity in respect to 1. Importantly, it was active for either wild-type or lamivudine-resistant HBV, as its target is host Hsc70 but not viral enzymes. LD(50) of 6b in mice was over 750 mg/kg in oral route. We consider compound 6b promising for further investigation.
authors.affiliation: Institute of Medicinal Biotechnology, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100050, China.
authors.forename: Li-Mei
authors.initials: LM
authors.lastname: Gao
authors.forename: Yan-Xing
authors.initials: YX
authors.lastname: Han
authors.forename: Yu-Ping
authors.initials: YP
authors.lastname: Wang
authors.forename: Yu-Huan
authors.initials: YH
authors.lastname: Li
authors.forename: Yong-Qiang
authors.initials: YQ
authors.lastname: Shan
authors.forename: Xin
authors.initials: X
authors.lastname: Li
authors.forename: Zong-Gen
authors.initials: ZG
authors.lastname: Peng
authors.forename: Chong-Wen
authors.initials: CW
authors.lastname: Bi
authors.forename: Tian
authors.initials: T
authors.lastname: Zhang
authors.forename: Na-Na
authors.initials: NN
authors.lastname: Du
authors.forename: Jian-Dong
authors.initials: JD
authors.lastname: Jiang
authors.forename: Dan-Qing
authors.initials: DQ
authors.lastname: Song
mesh_terms: D000284:Administration, Oral; D000470:Alkaloids / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D015536:Down-Regulation; D015195:Drug Design; D024882:Drug Resistance, Viral; D050883:HSC70 Heat-Shock Proteins / Q000235:genetics / Q000378:metabolism*; D056945:Hep G2 Cells; D006515:Hepatitis B virus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D019259:Lamivudine / Q000494:pharmacology; D007928:Lethal Dose 50; D051379:Mice; D008968:Molecular Conformation; D011807:Quinolizines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology; D012333:RNA, Messenger / Q000378:metabolism; D013329:Structure-Activity Relationship; D000093842:Matrines
chemical_list: D000470:Alkaloids; D000998:Antiviral Agents; D050883:HSC70 Heat-Shock Proteins; D019259:Lamivudine; D011807:Quinolizines; D012333:RNA, Messenger; C037573:oxymatrine; D000093842:Matrines