Synthesis of novel hybrids of pyrazole and coumarin as dual inhibitors of COX-2 and 5-LOX |
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Authors: | Fa-Qian Shen Zhong-Chang Wang Song-Yu Wu Shen-Zhen Ren Ruo-Jun Man Bao-Zhong Wang Hai-Liang Zhu |
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Institution: | State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210046, People’s Republic of China;Elion Nature Biological Technology Co., Ltd, 16 Hengtong Road, Nanjing 210038, People’s Republic of China |
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Abstract: | 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 μM for COX-2, IC50 = 0.87 ± 0.07 μM for 5-LOX, IC50 = 4.48 ± 0.57 μM against A549) showed preliminary superiority compared with the positive controls Celecoxib (IC50 = 0.41 ± 0.28 μM for COX-2, IC50 = 7.68 ± 0.55 μM against A549) and Zileuton (IC50 = 1.35 ± 0.24 μM 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. |
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Keywords: | COX-2 5-LOX Pyrazole Coumarin Cancer |
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