Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents

doi:10.1016/j.bioorg.2023.106617

KIB OpenIR

	Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents
	Li,Tian-Ze; Yang,Xiao-Tong; Ma,Wen-Jing; Ma,Yun-Bao; Li,Feng-Jiao; Wang,Yong-Cui; Chen,Ji-Jun
	2023
发表期刊	BIOORGANIC CHEMISTRY
ISSN	1090-2120
卷号	137 页码:106617
摘要	Artemyrianolide H (AH) is a germacrene-type sesquiterpenolid isolated from Artemisia myriantha, and showed potent cytotoxicity against three human hepatocellular carcinoma cell lines HepG2, Huh7, and SK-Hep-1 with IC50 values of 10.9, 7.2, and 11.9 & mu;M, respectively. To reveal structure-activity relationship, 51 artemyrianolide H derivatives including 19 dimeric analogs were designed, synthesized, and assayed for their cytotoxicity against three human hepatoma cell lines. Among them, 34 compounds were more active than artemyrianolide H and sorafenib on the three cell lines. Especially, compound 25 exhibited the most promising activity with IC50 values of 0.7 (HepG2), 0.6 (Huh7), and 1.3 & mu;M (SK-Hep-1), which were 15.5, 12.0, and 9.2-fold higher than that of AH and 16.4, 16.3 and 17.5-fold higher than that of sorafenib. Cytotoxicity evaluation on normal human liver cell lines (THLE-2) demonstrated good safety profile of compound 25 with SI of 1.9 (HepG2), 2.2 (Huh 7) and 1.0 (SK-Hep1). Further studies revealed that compound 25 dose-dependently arrested cells at G2/M phase which was correlated with the up-regulation of both cyclin B1 and p-CDK1, and induced apoptosis through the activation of mitochondrial pathways in HepG2 cells. In addition, the migratory and invasive abilities in HepG2 cells after treatment with 1.5 & mu;M of compound 25 were decreased by 89% and 86% with the increase of E-cadherin expression accompanied by the decrease of N-cadherin, vimentin expression. Bioinformatics analysis based on machine learning predicted that PDGFRA and MAP2K2 might be acting targets of compound 25, and SPR assays demonstrated compound 25 were bound with PDGFRA and MAP2K2 with KD value of 0.168 nM, and 8.49 & mu;M, respectively. This investigation proposed that compound 25 might be considered as a promising lead compound for the development of antihepatoma candidate.
关键词	Artemyrianolide H Germacranolide derivatives Antihepatoma activity Apoptosis DIMERS
学科领域	Biochemistry & Molecular Biology ; Chemistry
DOI	10.1016/j.bioorg.2023.106617
收录类别	SCI
WOS记录号	WOS:001015397000001
引用统计
文献类型	期刊论文
条目标识符	http://ir.kib.ac.cn/handle/151853/75475
专题	中国科学院昆明植物研究所
推荐引用方式 GB/T 7714	Li,Tian-Ze,Yang,Xiao-Tong,Ma,Wen-Jing,et al. Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents[J]. BIOORGANIC CHEMISTRY,2023,137:106617.
APA	Li,Tian-Ze.,Yang,Xiao-Tong.,Ma,Wen-Jing.,Ma,Yun-Bao.,Li,Feng-Jiao.,...&Chen,Ji-Jun.(2023).Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents.BIOORGANIC CHEMISTRY,137,106617.
MLA	Li,Tian-Ze,et al."Design, synthesis, and biological evaluation of artemyrianolide H derivatives as potential antihepatoma agents".BIOORGANIC CHEMISTRY 137(2023):106617.

条目包含的文件		下载所有文件
文件名称/大小	文献类型	版本类型	开放类型	使用许可
1-s2.0-S004520682300（9670KB）	期刊论文	出版稿	开放获取	CC BY-NC-SA	浏览下载