Discovery of novel hybrids of diaryl-1,2,4-triazoles and caffeic acid as dual inhibitors of cyclooxygenase-2 and 5-lipoxygenase for cancer therapy

Hao Cai, Xiaojing Huang, Shengtao Xu, Hao Shen, Pengfei Zhang, Yue Huang, Jieyun Jiang, Yijun Sun, Bo Jiang, Xiaoming Wu, Hequan Yao, Jingyi Xu

Research output: Contribution to journalArticlepeer-review

76 Scopus citations


Inflammation plays a key role in cancer initiation and propagation. Cyclooxygenase-2 (COX-2) and 5-lipoxygenase (5-LOX), two important enzymes in inflammatory responses are up-regulated in various tumor types. Dual inhibition of COX-2 and 5-LOX constitutes a rational concept for the design of more efficacious anti-tumor agents with an improved safety profile. We have previously reported a series of diaryl-1,2,4-triazole derivatives as selective COX-2 inhibitors. Herein, we hybridized the diaryl-1,2,4-triazoles with caffeic acid (CA) which was reported to display 5-LOX inhibitory and anti-tumor activities, affording a novel class of COX-2/5-LOX dual inhibitors as anti-tumor drug candidates. Most of these compounds exhibited potent COX-2/5-LOX inhibitory and antiproliferative activities in vitro. And the most potent compound 22b could significantly inhibit tumor growth in vivo. Furthermore, mechanistic investigation showed that the representative compound 15c blocked cell cycle in G2 phase and induced apoptosis in human non-small cell lung cancer A549 cells in a dose-dependent manner. Our preliminary investigation results would provide new clues for the cancer theatment with COX-2/5-LOX dual inhibitors.

Original languageEnglish
Pages (from-to)89-103
Number of pages15
JournalEuropean Journal of Medicinal Chemistry
StatePublished - Jan 27 2016

Bibliographical note

Funding Information:
This study was supported by the grants from State Key Laboratory of Natural Medicines, China Pharmaceutical University (No. SKLNMZZCX201404 ), Natural Science Foundation of Jiangsu Province (No. BK20130645 ), Huahai Pharmaceutical Graduate Innovation Fund (No. CX14B-005HH ) and Innovation project of Jiangsu Province (No. KYLX15-0636 ). We appreciate Prof. Luhua Lai of Peking University for direction of comparative modeling of 5-LOX.

Publisher Copyright:
© 2015 Elsevier Masson SAS.


  • 5-Lipoxygenase
  • Anti-tumor activity
  • Caffeic acid
  • Cyclooxygenase-2
  • Diaryl-1,2,4-Triazoles

ASJC Scopus subject areas

  • Pharmacology
  • Drug Discovery
  • Organic Chemistry


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