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

Tian-Ze Li; Xiao-Tong Yang; Wen-Jing Ma; Yun-Bao Ma; Feng-Jiao Li; Yong-Cui Wang; Ji-Jun Chen

doi:10.1016/j.bioorg.2023.106617

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

Bioorg Chem. 2023 Aug:137:106617. doi: 10.1016/j.bioorg.2023.106617. Epub 2023 May 22.

Authors

Tian-Ze Li¹, Xiao-Tong Yang¹, Wen-Jing Ma², Yun-Bao Ma¹, Feng-Jiao Li², Yong-Cui Wang¹, Ji-Jun Chen³

Affiliations

¹ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China.
² State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China.
³ State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201, PR China; University of Chinese Academy of Sciences, Beijing 100049, PR China. Electronic address: chenjj@mail.kib.ac.cn.

PMID: 37267793
DOI: 10.1016/j.bioorg.2023.106617

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 µM, 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 µM (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 μM 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 K_D value of 0.168 nM, and 8.49 µM, respectively. This investigation proposed that compound 25 might be considered as a promising lead compound for the development of antihepatoma candidate.

Keywords: Antihepatoma activity; Apoptosis; Artemyrianolide H; Germacranolide derivatives.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Antineoplastic Agents*
Apoptosis
Carcinoma, Hepatocellular* / drug therapy
Cell Line, Tumor
Cell Proliferation
Drug Screening Assays, Antitumor
Hep G2 Cells
Humans
Liver Neoplasms* / pathology
Sorafenib / pharmacology
Structure-Activity Relationship

Substances

Sorafenib
Antineoplastic Agents