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

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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

41 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)428-442
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
Publication statusPublished - 1 Feb 2019


  • Antitumor
  • Colchicine binding site
  • Indole
  • Microtubule
  • Quinoline
  • Tubulin inhibitor

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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