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Design, Synthesis, and Biological Evaluation of Pyrazoline‐Based Hydroxamic Acid Derivatives as Aminopeptidase N (APN) Inhibitors
Author(s) -
Cao Jiangying,
Zang Jie,
Ma Chunhua,
Li Xiaoguang,
Hou Jinning,
Li Jin,
Huang Yongxue,
Xu Wenfang,
Wang Binghe,
Zhang Yingjie
Publication year - 2018
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201700690
Subject(s) - angiogenesis , pyrazoline , umbilical vein , chemistry , ic50 , hydroxamic acid , in vitro , metastasis , aminopeptidase , biochemistry , stereochemistry , cancer research , pharmacology , cancer , biology , amino acid , leucine , organic chemistry , genetics
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‐1 H ‐pyrazole‐1‐carboxamide (compound 13 e ) showed the best APN inhibition with an IC 50 value of 0.16±0.02 μ m , which is more than one order of magnitude lower than that of bestatin (IC 50 =9.4±0.5 μ m ). 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.