新型小分子类肽氨肽酶N抑剂的设计、合成与初步活性评价 精灵论文.docVIP

新型小分子类肽氨肽酶 N 抑制剂的设计、合 成与初步活性评价 李荀 （山东大学药学院，济南 250012） 摘要：目的设计合成 L-异谷氨酰胺类小分子类肽化合物，体外筛选其氨肽酶 N (APN)及 MMP-2 的抑制活性，研究构-效关系。方法通过“拼接原理”，经缩合等反应合成小分子类肽 衍生物，采用体外抑酶活性实验测定目标化合物抑制 APN 与 MMP-2 的活性。结果合成了 22 个未见文献报道的化合物，结构经红外光谱、核磁共振氢谱、质谱确证。结论这类化合 物的氨肽酶 N 抑制活性显著高于 MMP-2，为选择性较高的氨肽酶 N 抑制剂。其中，化合物 8 (IC50 = 10.2 　 0.9 　M)的活性显著高于阳性对照药 Bestatin (IC50 = 13.1 　 0.7 　M),有望 成为先导物做进一步的研究。 关键词： 药物化学；APN/CD13; 抑制剂; Peptidomimetic; Anticancer Design, Synthesis and Preliminary Activity Evaluation of Novel Peptidomimetics as Aminopeptidase N/CD13 Inhibitors Li Xun (College of Pharmacy, Shandong University, Jinan 250012) Abstract: Aim To design and synthesize novel peptidomimetic analogues evaluated their inhibitory activities against aminopeptidase N (APN/CD13) and matrix metalloproteinase-2 (MMP-2). Methods According to the “combination principles”, peptidomimetic analogues were synthesized through condensation reaction, and their enzymatic inhibitory activities were assayed in vitro. Results 22 peptidomimetic APN inhibitors were prepared which have not been reported in literatures. Their structures were confirmed by IR, 1H-NMR, and MS. Conclusion Most of the compounds displayed selective inhibition against APN as compared with MMP-2, with IC50 values in micromole range. Within this series, compound 8 (IC50 = 10.2 　 0.9 　M) demonstrated comparable APN inhibitory activities as compared with the positive control bestatin (IC50 = 13.1 　 0.7 　M), which may provide a promising lead for further molecular optimizations. Key words: Medicinal Chemistry; APN/CD13; inhibitor; Peptidomimetic; Anticancer 0 引言 氨肽酶 N (APN, EC 3.4.11.2)是一种含锌离子的膜结合型外肽酶, 已经证明其在肿瘤细 胞表面大量表达，对肿瘤的侵袭和血管生成有重要的作用[1,2]。此外，它还能够表达于抗原 递呈细胞表面，降解多种免疫活性物质，使机体免疫力下降，削弱巨噬细胞和 NK 细胞对肿 瘤细胞的识别和杀伤能力[3,4]。该酶还可降解细胞外基质（ECM）的主要成分，促进肿瘤细 胞的生长和转移[5,6]。因此，抑制该酶的活性就可对肿瘤的侵袭和转移以及血管生成进行有 效地控制，同时增强粒细胞的趋化性，提高机体的免疫能力，进而可能成为有效的抗癌或抗 炎药物[7-9]。截至目前，已经有多种 APN 抑制剂类药物进入临床[10]，其中，Bestatin 作为抗 白血病的治疗药物已经在日本上市多年[11]，本实验将采用其作为阳性对照[12]。 基金项目：博士点青年基金（20070422061