2. Academic Validation
  3. Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents

Design, synthesis and evaluation of novel diaryl-1,5-diazoles derivatives bearing morpholine as potent dual COX-2/5-LOX inhibitors and antitumor agents

  • Eur J Med Chem. 2019 May 1:169:168-184. doi: 10.1016/j.ejmech.2019.03.008.
Zhang Li 1,  Zhong-Chang Wang 2,  Xin Li 1,  Muhammad Abbas 1,  Song-Yu Wu 1,  Shen-Zhen Ren 1,  Qi-Xing Liu 1,  Yi Liu 1,  Peng-Wen Chen 3,  Yong-Tao Duan 4,  Peng-Cheng Lv 5,  Hai-Liang Zhu 6
Affiliations

Affiliations

  • 1 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China.
  • 2 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China. Electronic address: wangzhongchang2006@163.com.
  • 3 School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, 210023, PR China.
  • 4 Henan Provincial Key Laboratory of Children's Genetics and Metabolic Diseases, Zhengzhou Children's Hospital, Zhengzhou, 450018, PR China.
  • 5 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China. Electronic address: pengcheng.lui@gmail.com.
  • 6 State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing, 210023, PR China. Electronic address: zhuhl@nju.edu.cn.
PMID: 30877972 DOI: 10.1016/j.ejmech.2019.03.008
Abstract

In this paper, 41 hybrid compounds containing diaryl-1,5-diazole and morpholine structures acting as dual COX-2/5-LOX inhibitors have been designed, synthesized and biologically evaluated. Most of them showed potent antiproliferative activities and COX-2/5-LOX inhibitory in vitro. Among them, compound A33 displayed the most potency against Cancer cell lines (IC50 = 6.43-10.97 μM for F10, HeLa, A549 and MCF-7 cells), lower toxicity to non-cancer cells than celecoxib (A33: IC50 = 194.01 μM vs.celecoxib: IC50 = 97.87 μM for 293T cells), and excellent inhibitory activities on COX-2 (IC50 = 0.17 μM) and 5-LOX (IC50 = 0.68 μM). Meanwhile, the molecular modeling study was performed to position compound A33 into COX-2 and 5-LOX active sites to determine the probable binding models. Mechanistic studies demonstrated that compound A33 could block cell cycle in G2 phase and subsequently induced Apoptosis of F10 cells. Furthermore, compound A33 could significantly inhibit tumor growth in F10-xenograft mouse model, and pharmacokinetic study of compound A33 indicated that it showed better stability in vivo. In general, compound A33 could be a promising candidate for Cancer therapy.

Keywords

5-Lipoxygenase; Anticancer; Cyclooxygenase-2; Diaryl-1,5-diazoles; Morpholine.

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