Design, Synthesis and Structure-Activity Relationship Optimization of Lycorine Derivatives for HCV Inhibition

作者：Chen, Duozhi; Cai, Jieyun; Cheng, Junjun; Jing, Chenxu; Yin, Junlin; Jiang, Jiandong; Peng, Zonggen; Hao, Xiaojiang^*

来源：Scientific Reports, 2015, 5(1): 14972.

DOI：10.1038/srep14972

• PROTEASE INHIBITORS

Lycorine is reported to be a multifunctional compound. We previously showed that lycorine is an HCV inhibitor with strong activity. Further research on the antivirus mechanism indicated that lycorine does not affect the enzymes that are indispensable to HCV replication but suppresses the expression of Hsc70 in the host cell to limit HCV replication. However, due to the cytotoxicity and apoptosis induction of lycorine, lycorine is unsafe to be a anti-HCV agent for clinical application. As a result of increasing interest, its structure was optimized for the first time and a novel series of lycorine derivatives was synthesized, all of which lost their cytotoxicity to different degrees. Structure-activity analysis of these compounds revealed that disubstitution on the free hydroxyl groups at C1 and C2 and/or degradation of the benzodioxole group would markedly reduce the cytotoxicity. Furthermore, an alpha, beta-unsaturated ketone would improve the HCV inhibitory activity of lycorine. The C3-C4 double bond is crucial to the anti-HCV activity because hydrogenation of this double bond clearly weakened HCV inhibition.

• 出版日期2015-10-7
• 单位植物化学与西部植物资源持续利用国家重点实验室; 云南中医药大学; 中国医学科学院医药生物技术研究所; 中国科学院昆明植物研究所