Design,Synthesis, and Biological Evaluation of Pyrazoline‐Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors |
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| Authors: | Jiangying Cao Jie Zang Chunhua Ma Xiaoguang Li Jinning Hou Jin Li Yongxue Huang Prof Wenfang Xu Prof Binghe Wang Dr Yingjie Zhang |
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| Affiliation: | 1. Department of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan, China;2. Department of Chemistry and Center for Diagnostics and Therapeutics, Georgia State University, Atlanta, GA, USA |
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| Abstract: | Aminopeptidase N (APN) has been recognized as a target for anticancer treatment due to its overexpression on diverse malignant tumor cells and association with cancer invasion, metastasis and angiogenesis. Herein we describe the synthesis, biological evaluation, and structure–activity relationship study of two new series of pyrazoline analogues as APN inhibitors. Among these compounds, 5‐(2‐(2‐(hydroxyamino)‐2‐oxoethoxy)phenyl)‐3‐phenyl‐4,5‐dihydro‐1H‐pyrazole‐1‐carboxamide (compound 13 e ) showed the best APN inhibition with an IC50 value of 0.16±0.02 μm , which is more than one order of magnitude lower than that of bestatin (IC50=9.4±0.5 μm ). Moreover, compound 13 e was found to inhibit the proliferation of diverse carcinoma cells and to show potent anti‐angiogenesis activity. At the same concentration, compound 13 e presents significantly higher anti‐angiogenesis activity than bestatin in human umbilical vein endothelial cells (HUVECs) capillary tube formation assays. The putative binding mode of 13 e in the active site of APN is also discussed. |
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| Keywords: | aminopeptidase N anti-angiogenesis antitumor agents inhibitors pyrazoline |
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