Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors

Shuai, Wen; Li, Xinnan; Li, Wenlong; Xu, Feijie; Lu, Lixue; Yao, Hong; Yang, Limei; Zhu, Huajian; Xu, Shengtao; Zhu, Zheying; Xu, Jinyi

Abstract

A series of novel isocombretapyridines were designed and synthesized based on a lead compound isocombretastatin A-4 (isoCA-4) by replacing 3,4,5-trimethoxylphenyl with substituent pyridine nucleus. The MTT assay results showed that compound 20a possessed the most potent activities against all tested cell lines with IC50 values at nanomolar concentration ranges. Moreover, 20a inhibited tubulin polymerization at a micromolar level and also displayed potent anti-vascular activity in vitro. Further mechanistic studies were conducted to demonstrate that compound 20a could bind to the colchicine site of tubulin,and disrupte the cell microtubule networks, induce G2/M phase arrest, promote apoptosis and depolarize mitochondria of K562 cells in a dose-dependent manner. Notably, 20a exhibited more potent tumor growth inhibition activity with 68.7% tumor growth inhibition than that of isoCA-4 in H22 allograft mouse model without apparent toxicity. The present results suggested that compound 20a may serve as a promising potent microtubule-destabilizing agent candidate for the development of therapeutics to treat cancer.

Citation

Shuai, W., Li, X., Li, W., Xu, F., Lu, L., Yao, H., …Xu, J. (2020). Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors. European Journal of Medicinal Chemistry, 197, Article 112308. https://doi.org/10.1016/j.ejmech.2020.112308

• Journal Article Type: Article
• Acceptance Date: Apr 2, 2020
• Online Publication Date: Apr 19, 2020
• Publication Date: 2020-07
• Deposit Date: Jul 5, 2020
• Publicly Available Date: Apr 20, 2021
• Journal: European Journal of Medicinal Chemistry
• Print ISSN: 0223-5234
• Publisher: Elsevier
• Peer Reviewed: Peer Reviewed
• Volume: 197
• Article Number: 112308
• DOI: https://doi.org/10.1016/j.ejmech.2020.112308
• Keywords: Organic Chemistry; Pharmacology; Drug Discovery; General Medicine
• Public URL: https://nottingham-repository.worktribe.com/output/4752183
• Publisher URL: https://www.sciencedirect.com/science/article/abs/pii/S0223523420302774?via%3Dihub
• Additional Information: This article is maintained by: Elsevier; Article Title: Design, synthesis and anticancer properties of isocombretapyridines as potent colchicine binding site inhibitors; Journal Title: European Journal of Medicinal Chemistry; CrossRef DOI link to publisher maintained version: https://doi.org/10.1016/j.ejmech.2020.112308; Content Type: article; Copyright: Crown Copyright © 2020 Published by Elsevier Masson SAS. All rights reserved.