Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma

	Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma
	Fan, Xiaohong; Deng, Jiedan; Shi, Tao; Wen, Huaixiu; Li, Junfang; Liang, Ziyi; Lei, Fang; Liu, Dan; Zhang, Honghua; Liang, Yan
刊名	BIOORGANIC CHEMISTRY
	2021
卷号	114
关键词	Hepatocellular carcinoma Topo I Evodiamine Cancer-associated fibroblasts (CAFs)
英文摘要	Topoisomerase has been found extremely high level of expression in hepatocellular carcinoma (HCC) and proven to promote the proliferation and survival of HCC. Cancer-associated fibroblasts (CAFs) as a kind of key reactive stromal cell that abundantly present in the microenvironment of HCC, could enhance the metastatic ability and drug resistance of HCC. Therefore, developing new drugs that address the above conundrums would be of the upmost significant in the fight against HCC. Evodiamine, as a multi-target natural product, has been found to exert various biological activities such as anti-cancer and anti-hepatic fibrosis via blocking topoisomerase, NF-kappa B, TGF-beta/HGF, and Smad2/3. Inspired by these facts, 15 evodiamine derivatives were designed and synthesized for HCC treatment by simultaneously targeting Topo I and CAFs. Most of them displayed preferable anti-HCC activities on three HCC cell lines and low cytotoxicity on one normal hepatic cell. In particular, compound 8 showed the best inhibitory effect on HCC cell lines and a good inhibition on Topo I in vitro. Meanwhile, it also induced obvious G(2)/M arrest and apoptosis, and significantly decreased the migration and invasion capacity of HCC cells. In addition, compound 8 down-regulated the expression of type I collagen in the activated HSC-T6 cells, and induced the apoptosis of activated HSC-T6 cells. In vivo studies demonstrated that compound 8 markedly decreased the volume and weight of tumor (TGI = 40.53%). In vitro and in vivo studies showed that its effects were superior to those of evodiamine. This preliminary attempt may provide a promising strategy for developing anti-HCC lead compounds taking effect through simultaneous inhibition on Topo I and CAFs.
内容类型	期刊论文
源URL	[http://210.75.249.4/handle/363003/60730]
专题	西北高原生物研究所_中国科学院西北高原生物研究所
推荐引用方式 GB/T 7714	Fan, Xiaohong,Deng, Jiedan,Shi, Tao,et al. Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma[J]. BIOORGANIC CHEMISTRY,2021,114.
APA	Fan, Xiaohong.,Deng, Jiedan.,Shi, Tao.,Wen, Huaixiu.,Li, Junfang.,...&Wang, Zhen.(2021).Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma.BIOORGANIC CHEMISTRY,114.
MLA	Fan, Xiaohong,et al."Design, synthesis and bioactivity study of evodiamine derivatives as multifunctional agents for the treatment of hepatocellular carcinoma".BIOORGANIC CHEMISTRY 114(2021).