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

Eur J Med Chem. 2016 Jan 27:108:89-103. doi: 10.1016/j.ejmech.2015.11.013.

Hao Cai ¹, Xiaojing Huang ¹, Shengtao Xu ¹, Hao Shen ¹, Pengfei Zhang ¹, Yue Huang ¹, Jieyun Jiang ², Yijun Sun ³, Bo Jiang ¹, Xiaoming Wu ⁴, Hequan Yao ¹, Jingyi Xu ⁵

Affiliations

1 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
2 Department of Microbiology, Immunology and Molecular Genetics, University of Kentucky College of Medicine, Lexington, KY 40536, USA.
3 Drug Screening Center, Nanjing KeyGen Biotech. Co. Ltd., Nanjing 210012, China.
4 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: xmwu@cpu.edu.cn.
5 Department of Medicinal Chemistry, China Pharmaceutical University, 24 Tong Jia Xiang, Nanjing 210009, China; State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China. Electronic address: jinyixu@china.com.

PMID: 26638042 DOI: 10.1016/j.ejmech.2015.11.013

Abstract

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.

Keywords

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

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