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

doi:10.1016/j.bioorg.2023.106617

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	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
Source Publication	BIOORGANIC CHEMISTRY
ISSN	1090-2120
Volume	137 Pages:106617
Abstract	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.
Keyword	Artemyrianolide H Germacranolide derivatives Antihepatoma activity Apoptosis DIMERS
Subject Area	Biochemistry & Molecular Biology ; Chemistry
DOI	10.1016/j.bioorg.2023.106617
Indexed By	SCI
WOS ID	WOS:001015397000001
Citation statistics
Document Type	期刊论文
Identifier	http://ir.kib.ac.cn/handle/151853/75475
Collection	中国科学院昆明植物研究所
Recommended Citation 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.

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