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±0.16μM for COX-2, IC50=0.87±0.07μM for 5-LOX, IC50=4.48±0.57μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50=0.41±0.28μM for COX-2, IC50=7.68±0.55μM against A549) and Zileuton (IC50=1.35±0.24μM 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.
Keywords: 5-LOX; COX-2; Cancer; Coumarin; Pyrazole.
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