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.

中文翻译：

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基于吡唑啉的羟肟酸衍生物作为氨肽酶N（APN）抑制剂的设计，合成和生物学评估

氨肽酶N（APN）因其在各种恶性肿瘤细胞上的过度表达以及与癌症侵袭，转移和血管生成的关系而被公认为是抗癌治疗的靶标。在这里，我们描述了两个新系列的吡唑啉类似物作为APN抑制剂的合成，生物学评估和结构-活性关系研究。在这些化合物中，5-（2-（2-（羟氨基）-2-氧代乙氧基）苯基）-3-苯基-4,5-二氢-1 H-吡唑-1-羧酰胺（化合物13 e）显示出最佳的APN抑制的IC ₅₀值的0.16±0.02μ米，这是数量级的多于一个的顺序比的苯丁抑制素降低（IC ₅₀ = 9.4±0.5μ米）。此外，化合物13 e被发现可以抑制多种癌细胞的增殖并显示出强大的抗血管生成活性。在相同浓度下，化合物13e的礼物显著更高的抗血管生成活性比苯丁抑制素在人脐静脉内皮细胞（HUVECs）的毛细管形成测定。还讨论了APN活性位点中13 e的假定结合方式。