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

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

Research output: Journal article publicationJournal articleAcademic researchpeer-review

19 Citations (Scopus)

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.

Original languageEnglish
Pages (from-to)1-14
Number of pages14
JournalEuropean Journal of Medicinal Chemistry
Volume173
DOIs
Publication statusPublished - 1 Jul 2019

Keywords

  • anti-vascular
  • Antitumor
  • Chalcone
  • Colchicine site
  • Microtubule-destabilizing agent
  • pyridine

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry

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