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Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents

Lu, Lixue; Zhang, Hengyuan; Liu, Jie; Liu, Yang; Wang, Yiwei; Xu, Shengtao; Zhu, Zheying; Xu, Jinyi

Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents Thumbnail


Authors

Lixue Lu

Hengyuan Zhang

Jie Liu

Yang Liu

Yiwei Wang

Shengtao Xu

ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu



Abstract

A series of C-23 modified 23-hydroxybetulinic acid (HBA) derivatives were synthesized and evaluated for their antiproliferative activity against a panel of cancer cell lines (A2780, A375, B16, MCF-7 and HepG2). The biological screening results showed that most of the derivatives exhibited more potent antiproliferative activity than HBA, and compound 6e exhibited the most potent activity with IC50 values of 2.14 μM, 2.89 μM, and 3.97 μM against A2780, B16, and MCF-7 cells, respectively. Further anticancer mechanism studies revealed that compound 6e induced the generation of intracellular reactive oxygen species (ROS) and reduction of mitochondrial membrane potential (MMP) of B16 cells in a dose-dependent manner. Moreover, western blot analysis indicated that compound 6e downregulated the expression of anti-apoptotic protein Bcl-2 and upregulated the expression of proapoptotic protein Bax, activation of caspase 3 to induce cell apoptosis. Meanwhile, compound 6e significantly inhibited the phosphorylation of MEK, ERK, and Akt without affecting the expression of MEK, ERK, and Akt. Furthermore, the in vivo anti-tumor activity of 6e was validated (tumor inhibitory ratio of 68.4% at the dose of 30 mg/kg) in mice with B16 melanoma.

Citation

Lu, L., Zhang, H., Liu, J., Liu, Y., Wang, Y., Xu, S., …Xu, J. (2019). Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents. European Journal of Medicinal Chemistry, 182, Article 111659. https://doi.org/10.1016/j.ejmech.2019.111659

Journal Article Type Article
Acceptance Date Aug 28, 2019
Online Publication Date Aug 29, 2019
Publication Date Nov 15, 2019
Deposit Date Nov 27, 2019
Publicly Available Date Mar 28, 2024
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 182
Article Number 111659
DOI https://doi.org/10.1016/j.ejmech.2019.111659
Keywords 23-Hydroxybetulinic acid; Structural modification; Antiproliferative activity; Melanoma; Anticancer mechanism
Public URL https://nottingham-repository.worktribe.com/output/3407175
Publisher URL https://www.sciencedirect.com/science/article/pii/S0223523419308037?via%3Dihub
Additional Information This article is maintained by: Elsevier; Article Title: Synthesis, biological evaluation and mechanism studies of C-23 modified 23-hydroxybetulinic acid derivatives as anticancer agents; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2019.111659; Content Type: article; Copyright: © 2019 Elsevier Masson SAS. All rights reserved.

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