Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo

Zhu, Huajian; Zhu, Wenjian; Liu, Yang; Gao, Tian; Zhu, Jingjie; Tan, Yuchen; Hu, Han; Liang, Wenhao; Zhao, Lingyue; Chen, Jian; Zhu, Zheying; Chen, Jichao; Xu, Jinyi; Xu, Shengtao

Abstract

A series of novel stilbene-based derivatives were designed and synthesized as tubulin/HDAC dual-target inhibitors. Among forty-three target compounds, compound II-19k not only exhibited considerable antiproliferative activity in the hematological cell line K562 with IC50 value of 0.003 μM, but also effectively inhibited the growth of various solid tumor cell lines with IC50 values ranging from 0.005 to 0.036 μM. The mechanism studies demonstrated that II-19k could inhibit microtubules and HDACs at the cellular level, block cell cycle arrest at G2 phase, induce cell apoptosis, and reduce solid tumor cells metastasis. What's more, the vascular disrupting effects of compound II-19k were more pronounced than the combined administration of parent compound 8 and HDAC inhibitor SAHA. The in vivo antitumor assay of II-19k also showed the superiority of dual-target inhibition of tubulin and HDAC. II-19k significantly suppressed the tumor volume and effectively reduced tumor weight by 73.12% without apparent toxicity. Overall, the promising bioactivities of II-19k make it valuable for further development as an antitumor agent.

Citation

Zhu, H., Zhu, W., Liu, Y., Gao, T., Zhu, J., Tan, Y., Hu, H., Liang, W., Zhao, L., Chen, J., Zhu, Z., Chen, J., Xu, J., & Xu, S. (2023). Synthesis and bioevaluation of novel stilbene-based derivatives as tubulin/HDAC dual-target inhibitors with potent antitumor activities in vitro and in vivo. European Journal of Medicinal Chemistry, 257, Article 115529. https://doi.org/10.1016/j.ejmech.2023.115529

• Journal Article Type: Article
• Acceptance Date: May 25, 2023
• Online Publication Date: May 30, 2023
• Publication Date: Sep 5, 2023
• Deposit Date: Jul 3, 2023
• Publicly Available Date: May 31, 2024
• Journal: European Journal of Medicinal Chemistry
• Electronic ISSN: 1768-3254
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 257
• Article Number: 115529
• DOI: https://doi.org/10.1016/j.ejmech.2023.115529
• Keywords: Dual-target inhibitors, Tubulin, Antitumor, HDAC, Stilbene
• Public URL: https://nottingham-repository.worktribe.com/output/22173091
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523423004956?via%3Dihub