标题：Leucine ureido derivatives as aminopeptidase N inhibitors using click chemistry. Part II
作者：Cao, Jiangying; Zang, Jie; Kong, Xiujie; Zhao, Chunlong; Chen, Ting; Ran, Yingying; Dong, Hang; Xu, Wenfang; Zhang, Yingjie
作者机构：[Cao, Jiangying; Zang, Jie; Kong, Xiujie; Zhao, Chunlong; Chen, Ting; Ran, Yingying; Dong, Hang; Xu, Wenfang; Zhang, Yingjie] Shandong Univ, Sch Pharm 更多
通讯作者地址：[Zhang, YJ]Shandong Univ, Sch Pharmaceut Sci, Dept Med Chem, Jinan 250012, Shandong, Peoples R China.
来源：BIOORGANIC & MEDICINAL CHEMISTRY
关键词：Aminopeptidase N; CD13; Anti-angiogenesis; Anti-metastasis; Triazole
摘要：Aminopeptidase N (APN) has been proved to be deeply associated with cancer angiogenesis, metastasis and invasion. Therefore, APN gains increasing attention as a promising anti-tumor target. In the current study, we report the design, synthesis, biological evaluation and structure-activity relationship of one new series of leucine ureido derivatives containing the 1,2,3-triazole moiety. Among them, compound 31f was identified as the best APN inhibitor with IC50 value being two orders of magnitude lower than that of the positive control bestatin. Compound 31f possessed selective cytotoxicity to several tumor cell lines over the normal cell line human umbilical vein endothelial cells (HUVECs). Notably, when combined with 5-fluorouracil (5-Fu), 31f exhibited synergistic anti-proliferation effect against several tumor cell lines. At the same concentration, 31f exhibited much better anti-angiogenesis activities than bestatin in the HUVECs capillary tube formation assay and the rat thoracic aorta rings test. In the in vitro anti-invasion assay, 31f also exhibited superior potency over bestatin. Moreover, considerable in vivo antitumor potencies of 31f alone or in combination with 5-Fu were observed without significant toxic signs in a mouse heptoma H22 tumor transplant model.