期刊
BIOORGANIC & MEDICINAL CHEMISTRY LETTERS
卷 27, 期 16, 页码 3653-3660出版社
PERGAMON-ELSEVIER SCIENCE LTD
DOI: 10.1016/j.bmcl.2017.07.020
关键词
COX-2; 5-LOX; Pyrazole; Coumarin; Cancer
资金
- National Science & Technology Supporting Project [2015BAD16B07]
- Public Science and Technology Research Fund Project of Ocean [201505023]
- Science & Technology Bureau of Lianyungang City of Jiangsu Province [CXY1412]
In our previous study, we designed a series of pyrazole derivatives as novel COX-2 inhibitors. In order to obtain novel dual inhibitors of COX-2 and 5-LOX, herein we designed and synthesized 20 compounds by hybridizing pyrazole with substituted coumarin who was reported to exhibit 5-LOX inhibition to select potent compounds using adequate biological trials sequentially including selective inhibition of COX-2 and 5-LOX, anti-proliferation in vitro, cells apoptosis and cell cycle. Among them, the most potent compound 11g (IC50= 0.23 +/- 0.16 mu M for COX-2, IC50 = 0.87 +/- 0.07 mu M for 5-LOX, IC50 = 4.48 +/- 0.57 mu M against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50 = 0.41 +/- 0.28 mu M for COX-2, IC50 = 7.68 +/- 0.55 mu M against A549) and Zileuton (IC50 = 1.35 +/- 0.24 mu M for 5-LOX). Further investigation confirmed that 11g could induce human non small cell lung cancer A549 cells apoptosis and arrest the cell cycle at G2 phase in a dose-dependent manner. Our study might contribute to COX-2, 5-LOX dual inhibitors thus exploit promising novel cancer prevention agents. (C) 2017 Elsevier Ltd. All rights reserved.
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