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Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site

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

Authors

Wenlong Li

Wen Shuai

Honghao Sun

Feijie Xu

Yi Bi

Jinyi Xu

Cong Ma

Hequan Yao

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

Shengtao Xu



Abstract

A series of novel isocombretastatin A-4 (isoCA-4) analogs were designed and synthesized by replacing 3,4,5-trimethoylphenyl and isovanillin of isoCA-4 with quinoline and indole moieties, respectively. The structure activity relationships (SARs) of these synthesized quinoline-indole derivatives have been intensively investigated. Two compounds 27c and 34b exhibited the most potent activities against five cancer cell lines with IC50 values ranging from 2 to 11 nM, which were comparable to those of Combretastatin A-4 (CA-4, 1). Further mechanism investigations revealed that 34b effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Further cellular mechanism studies elucidated that 34b disrupted cell microtubule networks, arrested the cell cycle at G2/M phase, induced apoptosis and depolarized mitochondria of K562 cells. Moreover, 34b displayed potent anti-vascular activity in both wound healing and tube formation assays. Importantly, 27c and 34b significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, suggesting that 27c and 34b deserve further research as potent antitumor agents for cancer therapy.

Journal Article Type Article
Publication Date Feb 1, 2019
Journal European Journal of Medicinal Chemistry
Print ISSN 0223-5234
Electronic ISSN 1768-3254
Publisher Elsevier
Peer Reviewed Peer Reviewed
Volume 163
Pages 428-442
APA6 Citation Li, W., Shuai, W., Sun, H., Xu, F., Bi, Y., Xu, J., …Xu, S. (2019). Design, synthesis and biological evaluation of quinoline-indole derivatives as anti-tubulin agents targeting the colchicine binding site. European Journal of Medicinal Chemistry, 163, 428-442. https://doi.org/10.1016/j.ejmech.2018.11.070
DOI https://doi.org/10.1016/j.ejmech.2018.11.070
Keywords Quinoline; Indole; Microtubule; Tubulin inhibitor; Colchicine binding site; Antitumor
Publisher URL https://www.sciencedirect.com/science/article/pii/S0223523418310298

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