Evaluation of anti-HCV activity and SAR study of (+)-lycoricidine through targeting of host heat-stress cognate 70 (Hsc70)

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• 作者：Duo-Zhi Chen^a ; ^b ; ^c ; Jian-Dong Jiang^d ; Ke-Qing Zhang^c ; Hong-Ping He^a ; Ying-Tong Di^a ; Yu Zhang^a ; Jie-Yun Cai^a ; ^b ; Lei Wang^a ; ^b ; Shun-Lin Li^a ; Ping Yi^e ; Zong-Gen Peng^d ; ^{pumcpzg@126.com} ; Xiao-Jiang Hao^a ; ^{haoxj@mail.kib.ac.cn}
• 关键词：(+)-Lycoricidine ; Heat-stress cognate 70 (Hsc70) ; Down-regulators ; Structure&ndash ; activity relationship (SAR) ; Anti-HCV activity
• 刊名：Bioorganic and Medicinal Chemistry Letters
• 出版年：2013
• 出版时间：1 May, 2013
• 年：2013
• 卷：23
• 期：9
• 页码：2679-2682
• 全文大小：555 K

文摘

The anti hepatitis C virus (HCV) activity of (+)-lycoricidine (1) was evaluated for the first time in this letter, yielding an EC₅₀ value of 0.55 nmol/mL and an selection index (SI) value of 12.72. Further studies indicated that 1 induced this effect by down-regulating host heat-stress cognate 70 (Hsc70) expression. In addition, 20 derivatives were designed and synthesised to investigate the basic structure-activity relationship (SAR) of the title compound. Several of these derivatives exhibit a good inhibition of HCV, such as compound 3 (EC₅₀ = 0.68 nmol/mL, SI = 33.86), compound 2d (EC₅₀ = 15 nmol/mL, SI = 12) and compound 5 (EC₅₀ = 33 nmol/mL, SI >10.91). Meanwhile, the experimental data suggest that the modification of certain groups of (+)-lycoricidine can reduce the cytotoxicity of the compounds.