Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities

Zhu, Huajian; Li, Wenlong; Shuai, Wen; Liu, Yang; Yang, Limei; Tan, Yuchen; Zheng, Tiandong; Yao, Hong; Xu, Jinyi; Zhu, Zheying; Yang, Dong-Hua; Chen, Zhe-Sheng; Xu, Shengtao

Abstract

A series of novel N-benzylbenzamide derivatives were designed and synthesized as tubulin polymerization inhibitors. Among fifty-one target compounds, compound 20b exhibited significant antiproliferative activities with IC50 values ranging from 12 to 27 nM against several cancer cell lines, and possessed good plasma stability and satisfactory physicochemical properties. Mechanism studies demonstrated that 20b bound to the colchicine binding site and displayed potent anti-vascular activity. Notably, the corresponding disodium phosphate 20b-P exhibited an excellent safety profile with the LD50 value of 599.7 mg/kg (i.v. injection), meanwhile, it significantly inhibited tumor growth and decreased microvessel density in liver cancer cell H22 allograft mouse model without obvious toxicity. Collectively, 20b and 20b-P are novel promising anti-tubulin agents with more druggable properties and deserve to be further investigated for cancer therapy.

Citation

Zhu, H., Li, W., Shuai, W., Liu, Y., Yang, L., Tan, Y., Zheng, T., Yao, H., Xu, J., Zhu, Z., Yang, D.-H., Chen, Z.-S., & Xu, S. (2021). Discovery of novel N-benzylbenzamide derivatives as tubulin polymerization inhibitors with potent antitumor activities. European Journal of Medicinal Chemistry, 216, Article 113316. https://doi.org/10.1016/j.ejmech.2021.113316

• Journal Article Type: Article
• Acceptance Date: Feb 17, 2021
• Online Publication Date: Feb 24, 2021
• Publication Date: Apr 15, 2021
• Deposit Date: Feb 27, 2021
• Publicly Available Date: Feb 25, 2023
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 216
• Article Number: 113316
• DOI: https://doi.org/10.1016/j.ejmech.2021.113316
• Keywords: Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/5353483
• Publisher URL: https://www.sciencedirect.com/science/article/pii/S0223523421001653?via%3Dihub