Institute of Medicinal Chemistry, School of Pharmaceutical Sciences, Shandong University, Jinan 250012, Shandong, China.
Fundam Clin Pharmacol. 2011 Apr;25(2):217-28. doi: 10.1111/j.1472-8206.2010.00844.x.
Aminopeptidase N (APN) plays an important role in tumor progression, which participates in the progress such as proliferation, attachment, angiogenesis, and tumor invasion. All of this makes APN as a good chemical therapeutic anti-tumor target. In this study, a series of chemically synthesized APN inhibitors were tested for the anti-tumor activities, and three most effective compounds were chosen according to the MTT assay. Then, the enzyme inhibitory, anti-tumor, specificity, angiogenesis, and invasion were determined to evaluate the activity of these three compounds. All compounds can markedly inhibit the enzyme activity of APN, angiogenesis of endothelial cells, and the invasion of ES-2 cells. And it had little effect on the viability of K562 which express low level of APN. This data indicated that the tested compounds were APN hit compounds. We also did kinetic assay to determine the inhibition constant and constructed a three-dimensional quantitative structure-activity relationship model to analyze the structure-activity relationship to direct the further design of novel APN inhibitors as anti-tumor agents. These data demonstrate that the tested compounds can be developed as novel candidates of anticancer agent.
天冬氨酰蛋白酶 N（APN）在肿瘤进展中发挥着重要作用，参与增殖、附着、血管生成和肿瘤侵袭等过程。这使得 APN 成为一种很好的化学治疗抗肿瘤靶点。在本研究中，我们测试了一系列化学合成的 APN 抑制剂的抗肿瘤活性，根据 MTT 测定结果选择了三种最有效的化合物。然后，我们测定了这些化合物的酶抑制、抗肿瘤、特异性、血管生成和侵袭活性，以评估这三种化合物的活性。所有化合物均能显著抑制 APN 的酶活性、内皮细胞的血管生成和 ES-2 细胞的侵袭，而对表达低水平 APN 的 K562 细胞的活力影响很小。这些数据表明，所测试的化合物是 APN 的有效化合物。我们还进行了动力学测定以确定抑制常数，并构建了三维定量构效关系模型来分析构效关系，以指导新型 APN 抑制剂作为抗肿瘤药物的进一步设计。这些数据表明，所测试的化合物可作为新型抗肿瘤候选药物进行开发。
