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

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., Zhu, Z., & 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: Aug 30, 2020
• 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.