2. Academic Validation
  3. Design, synthesis and biological evaluation of pyridine-chalcone derivatives as novel microtubule-destabilizing agents

Design, synthesis and biological evaluation of pyridine-chalcone derivatives as novel microtubule-destabilizing agents

  • Eur J Med Chem. 2019 Jul 1:173:1-14. doi: 10.1016/j.ejmech.2019.04.008.
Feijie Xu 1,  Wenlong Li 1,  Wen Shuai 1,  Limei Yang 1,  Yi Bi 2,  Cong Ma 3,  Hequan Yao 1,  Shengtao Xu 4,  Zheying Zhu 5,  Jinyi 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 Chemical Biology and Drug Discovery, Department of Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Kowloon, Hong Kong.
  • 4 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.
  • 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: jinyixu@china.com.
PMID: 30981112 DOI: 10.1016/j.ejmech.2019.04.008
Abstract

Further optimization of the trimethoxyphenyl scaffold of parent chalcone compound (2a) by introducing a pyridine ring afforded a series of novel pyridine-chalcone derivatives as potential anti-tubulin agents. All the target compounds were evaluated for their antiproliferative activities. Among them, representative compound 16f exhibited the most potent activity with the IC50 values ranging from 0.023 to 0.045 μM against a panel of Cancer cell lines. Further mechanism study results demonstrated that compound 16f effectively inhibited the microtubule polymerization by binding to the colchicine site of tubulin. Moreover, cellular mechanism studies disclosed that 16f caused G2/M phase arrest, induced cell Apoptosis and disrupted the intracellular microtubule network. Also, 16f reduced the cell migration and disrupted the capillary-like tube formation of human umbilical vein endothelial cells (HUVECs). Importantly, 16f significantly inhibited tumor growth in H22 xenograft models without apparent toxicity, which was stronger than the reference compound CA-4, indicating that it is worthy to investigate 16f as a potent microtubule-destabilizing agent for Cancer therapy.

Keywords

Antitumor; Chalcone; Colchicine site; Microtubule-destabilizing agent; anti-vascular; pyridine.

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