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Discovery of novel quinoline–chalcone derivatives as potent antitumor agents with microtubule polymerization inhibitory activity

Li, Wenlong; Xu, Feijie; Shuai, Wen; Sun, Honghao; Yao, Hong; Ma, Cong; Xu, Shengtao; Yao, Hequan; Zhu, Zheying; Yang, Dong-Hua; Chen, Zhe-Sheng; Xu, Jinyi

Authors

Wenlong Li

Feijie Xu

Wen Shuai

Honghao Sun

Hong Yao

Cong Ma

Shengtao Xu

Hequan Yao

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

Dong-Hua Yang

Zhe-Sheng Chen

Jinyi Xu



Abstract

© 2018 American Chemical Society. A series of novel quinoline-chalcone derivatives were designed, synthesized, and evaluated for their antiproliferative activity. Among them, compound 24d exhibited the most potent activity with IC 50 values ranging from 0.009 to 0.016 μM in a panel of cancer cell lines. Compound 24d also displayed a good safety profile with an LD 50 value of 665.62 mg/kg by intravenous injection, and its hydrochloride salt 24d-HCl significantly inhibited tumor growth in H22 xenograft models without observable toxic effects, which was more potent than that of CA-4. Mechanism studies demonstrated that 24d bound to the colchicine site of tubulin, arrested the cell cycle at the G2/M phase, induced apoptosis, depolarized mitochondria, and induced reactive oxidative stress generation in K562 cells. Moreover, 24d has potent in vitro antimetastasis and in vitro and in vivo antivascular activities. Collectively, our findings suggest that 24d deserves to be further investigated as a potent and safe antitumor agent for cancer therapy.

Journal Article Type Article
Publication Date Jan 24, 2019
Journal Journal of Medicinal Chemistry
Print ISSN 0022-2623
Electronic ISSN 1520-4804
Publisher American Chemical Society
Peer Reviewed Peer Reviewed
Volume 62
Issue 2
Pages 993-1013
APA6 Citation Li, W., Xu, F., Shuai, W., Sun, H., Yao, H., Ma, C., …Xu, J. (2019). Discovery of novel quinoline–chalcone derivatives as potent antitumor agents with microtubule polymerization inhibitory activity. Journal of Medicinal Chemistry, 62(2), 993-1013. https://doi.org/10.1021/acs.jmedchem.8b01755
DOI https://doi.org/10.1021/acs.jmedchem.8b01755
Keywords Molecular Medicine; Drug Discovery
Publisher URL https://pubs.acs.org/doi/10.1021/acs.jmedchem.8b01755

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