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Synthesis, molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site

Li, Wenlong; Sun, Honghao; Xu, Feijie; Shuai, Wen; Liu, Jie; Xu, Shengtao; Yao, Hequan; Ma, Cong; Zhu, Zheying; Xu, Jinyi

Authors

Wenlong Li

Honghao Sun

Feijie Xu

Wen Shuai

Jie Liu

Shengtao Xu

Hequan Yao

Cong Ma

ZHEYING ZHU Zheying.Zhu@nottingham.ac.uk
Associate Professor in International Pharmacy and Traditional Medicines

Jinyi Xu



Abstract

Twenty-two novel indole-vinyl sulfone derivatives were designed, synthesized and evaluated as tubulin polymerization inhibitors. The physicochemical and drug-likeness properties of all target compounds were predicted by Osiris calculations. All compounds were evaluated for their antiproliferative activities, among them, compound 7f exhibited the most potent activity against a panel of cancer cell lines, which was 2–7 folds more potent than our previously reported compound 4. Especially, 7f displayed about 8-fold improvement of selective index as compared with compound 4, indicating that 7f might have lower toxicity. Besides, 7f inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further investigations showed that compound 7f effectively disrupted microtubule network, caused cell cycle arrest at G2/M phase and induced cell apoptosis in K562 cells. Moreover, 7f reduced the cell migration and disrupted capillary-like tube formation in HUVEC cells. Importantly, the in vivo anti-tumor activity of 7f was validated in H22 liver cancer xenograft mouse model without apparent toxicity, suggesting that 7f is a promising anti-tubulin agent for cancer therapy.

Citation

Li, W., Sun, H., Xu, F., Shuai, W., Liu, J., Xu, S., …Xu, J. (2019). Synthesis, molecular properties prediction and biological evaluation of indole-vinyl sulfone derivatives as novel tubulin polymerization inhibitors targeting the colchicine binding site. Bioorganic Chemistry, 85, 49-59. https://doi.org/10.1016/j.bioorg.2018.12.015

Journal Article Type Article
Acceptance Date Dec 10, 2018
Online Publication Date Dec 10, 2018
Publication Date 2019-04
Deposit Date Jul 2, 2019
Journal Bioorganic Chemistry
Print ISSN 0045-2068
Electronic ISSN 1090-2120
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 85
Pages 49-59
DOI https://doi.org/10.1016/j.bioorg.2018.12.015
Keywords Tubulin inhibitor; Vinyl sulfone; Indole; Colchicine site; Drug-likeness
Public URL https://nottingham-repository.worktribe.com/output/2257651
Publisher URL https://www.sciencedirect.com/science/article/pii/S0045206818312914?via%3Dihub