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

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

  • Eur J Med Chem. 2019 Feb 1:163:428-442. doi: 10.1016/j.ejmech.2018.11.070.
Wenlong Li 1,  Wen Shuai 1,  Honghao Sun 1,  Feijie Xu 1,  Yi Bi 2,  Jinyi Xu 3,  Cong Ma 4,  Hequan Yao 1,  Zheying Zhu 5,  Shengtao Xu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China.
  • 2 School of Pharmacy, Key Laboratory of Molecular Pharmacology and Drug Evaluation, Yantai University, Yantai, 264005, PR China.
  • 3 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: jinyixu@china.com.
  • 4 State Key Laboratory of Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
  • 5 Division of Molecular Therapeutics & Formulation, School of Pharmacy, The University of Nottingham, University Park Campus, Nottingham, NG7 2RD, UK.
  • 6 State Key Laboratory of Natural Medicines and Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, PR China. Electronic address: cpuxst@163.com.
PMID: 30530194 DOI: 10.1016/j.ejmech.2018.11.070
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.

Keywords

Antitumor; Colchicine binding site; Indole; Microtubule; Quinoline; Tubulin inhibitor.

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