Design, synthesis and biological evaluation of vinyl selenone derivatives as novel microtubule polymerization inhibitors

Zhu, Huajian; Sun, Honghao; Liu, Yang; Duan, Yiping; Liu, Jie; Yang, Xue; Li, Wenlong; Qin, Shuai; Xu, Shengtao; Zhu, Zheying; Xu, Jinyi

Abstract

A series of novel vinyl selenone derivatives were designed, synthesized and evaluated as the tubulin polymerization inhibitors using a bioisosteric strategy. Among them, the representative compound 11k exhibited satisfactory anti-proliferative activities with IC50 values ranging from 0.287 to 0.621 μM against a panel of cancer cell lines. Importantly, 11k displayed more potent in vivo antitumor activity than the positive control paclitaxel, CA-4 and parent compound 4 without apparent toxicity, which was presumably ascribed to the antiangiogenic, antiproliferative and selective effects of selenium, along with the unique physiological activity of indole skeleton, which were both introduced into the structure of target compounds. Further mechanism study demonstrated that compound 11k showed potent activity in tubulin polymerization inhibition with IC50 value of 1.82 μM. Moreover, cellular mechanism studies disclosed that 11k blocked cell cycle arrest at G2/M phase, induced cell apoptosis and depolarized mitochondria of K562 cells. Meanwhile, 11k reduced the cell migration and had potent vascular disrupting activity. In summary, 11k could serve as a promising lead for the development of more efficient microtubule polymerization inhibitors for cancer therapy.

Citation

Zhu, H., Sun, H., Liu, Y., Duan, Y., Liu, J., Yang, X., Li, W., Qin, S., Xu, S., Zhu, Z., & Xu, J. (2020). Design, synthesis and biological evaluation of vinyl selenone derivatives as novel microtubule polymerization inhibitors. European Journal of Medicinal Chemistry, 207, Article 112716. https://doi.org/10.1016/j.ejmech.2020.112716

• Journal Article Type: Article
• Acceptance Date: Jul 22, 2020
• Online Publication Date: Aug 17, 2020
• Publication Date: Dec 1, 2020
• Deposit Date: Jan 27, 2024
• Journal: European Journal of Medicinal Chemistry
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 207
• Article Number: 112716
• DOI: https://doi.org/10.1016/j.ejmech.2020.112716
• Keywords: Selenium, Vinyl selenone, Bioisosteric strategy, Tubulin inhibitors, Antitumor
• Public URL: https://nottingham-repository.worktribe.com/output/30152812
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523420306887?via%3Dihub