Synthesis and anti-fibrotic effects of santamarin derivatives as cytotoxic agents against hepatic stellate cell line LX2

Bioorg Med Chem Lett. 2021 Jun 1:41:127994. doi: 10.1016/j.bmcl.2021.127994.

Jin-Ping Wang ¹, Tian-Ze Li ², Xiao-Yan Huang ², Chang-An Geng ², Cheng Shen ², Jin-Jin Sun ¹, Dong Xue ³, Ji-Jun Chen ⁴

Affiliations

1 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China; Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710062, People's Republic of China.
2 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China.
3 Key Laboratory of Applied Surface and Colloid Chemistry, Ministry of Education and School of Chemistry and Chemical Engineering, Shaanxi Normal University, Xi'an 710062, People's Republic of China. Electronic address: xuedong_welcome@snnu.edu.cn.
4 State Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Yunnan Key Laboratory of Natural Medicinal Chemistry, Kunming 650201, People's Republic of China; University of Chinese Academy of Sciences, Beijing 100049, People's Republic of China. Electronic address: chenjj@mail.kib.ac.cn.

PMID: 33775837 DOI: 10.1016/j.bmcl.2021.127994

Abstract

Liver fibrosis is a final result of extensive deposition of extracellular matrix (ECM) and starts with the activation and proliferation of hepatic stellate cells (HSCs). Our previous study showed that eudesmane sesquiterpenoid santamarin had cytotoxicity against hepatic stellate cell line LX2 (HSC-LX2) with IC₅₀ values of 16.5 ± 0.7 μM. To explore the structure-activity relationships, twenty-six derivatives were synthesized by modifying the hydroxyl group, double-bond and unsaturated lactone. Cytotoxicity evaluation suggested that eight derivatives (6, 9, 13, 17, 20 and 25-27) increased activity against HSC-LX2. Especially, derivatives 17, 20 and 25 displayed obvious cytotoxicity with IC₅₀ values of 6.4 ± 0.4, 4.6 ± 0.1, and 3.5 ± 0.1 μM, which were 3 to 5-fold higher than santamarin. Preliminary mechanisms study revealed that the active compound 20 exhibited more than 8-fold and 6-fold enhancement of inhibitory effect on the deposition of human hyaluronic acid (HA) and human laminin (HL) with IC₅₀ values of 7.6 ± 0.6 and 3.3 ± 1.2 μM.

Keywords

Anti-fibrotic effects; Extracellular matrix; HSC-LX2; Santamarin derivatives.

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