Design, Synthesis, and Biological Evaluation of Novel Evodiamine Derivatives as Potential Antihepatocellular Carcinoma Agents
- Fang Lei
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- Yongxia Xiong
Yongxia XiongSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, ChinaMore by Yongxia Xiong
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- Yuqing Wang
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- Honghua Zhang
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- Ziyi Liang
Ziyi LiangState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, ChinaMore by Ziyi Liang
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- Junfang Li
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- Yiyue Feng
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- Xiangyong Hao*
Xiangyong Hao*Email: [email protected]. Tel: (+86)13679469257. Fax: (+86)931 8281683.Department of General Surgery, Gansu Provincial Hospital, Lanzhou 730000, ChinaMore by Xiangyong Hao
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- Zhen Wang*
Zhen Wang*Email: [email protected]. Tel: (+86)18298311530. Fax: (+86)931 8915686.School of Pharmacy, Lanzhou University, Lanzhou 730000, ChinaSchool of Pharmaceutical Science, Hengyang Medical School, University of South China, Hengyang, Hunan 421001, ChinaState Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, Lanzhou 730000, ChinaMore by Zhen Wang
Abstract
Evodiamine has many biological activities. Herein, we synthesize 23 disubstituted derivatives of N14-phenyl or the E-ring of evodiamine and conduct systematic structure–activity relationship studies. In vitro antiproliferative activity indicated that compounds F-3 and F-4 dramatically inhibited the proliferation of Huh7 (IC50 = 0.05 or 0.04 μM, respectively) and SK-Hep-1 (IC50 = 0.07 or 0.06 μM, respectively) cells. Furthermore, compounds F-3 and F-4 could double inhibit topoisomerases I and II, inhibit invasion and migration, block the cell cycle to the G2/M stage, and induce apoptosis as well. Additionally, compounds F-3 and F-4 could also inhibit the activation of HSC-T6 and reduce the secretion of collagen type I to slow down the progression of liver fibrosis. Most importantly, compound F-4 (TGI = 60.36%) inhibited tumor growth more significantly than the positive drug sorafenib. To sum up, compound F-4 has excellent potential as a strong candidate for the therapy of hepatocellular carcinoma.
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- Zhen Wang, Yongxia Xiong, Ying Peng, Xi Zhang, Shuang Li, Yan Peng, Xue Peng, Linsheng Zhuo, Weifan Jiang. Natural product evodiamine-inspired medicinal chemistry: Anticancer activity, structural optimization and structure-activity relationship. European Journal of Medicinal Chemistry 2023, 247 , 115031. https://doi.org/10.1016/j.ejmech.2022.115031