- Design and synthesis of oxymatrine analogues overcoming drug resistance in hepatitis B virus through targeting host heat stress cognate 70
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Heat-stress cognate 70 (Hsc70is a host protein required for hepatitis B virus (HBVreplication, and oxymatrine (1suppresses 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 (ithe oxygen atom at the 1-position was not essential, (iiincreasing electron density on the ring D reduced the activity, and (iiiintroducing 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. LD50 of 6b in mice was over 750 mg/kg in oral route. We consider compound 6b promising for further investigation.
- Gao, Li-Mei,Han, Yan-Xing,Wang, Yu-Ping,Li, Yu-Huan,Shan, Yong-Qiang,Li, Xin,Peng, Zong-Gen,Bi, Chong-Wen,Zhang, Tian,Du, Na-Na,Jiang, Jian-Dong,Song, Dan-Qing
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p. 869 - 876
(2011/04/18)
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