扁桃酰氨基酸类氨肽酶N抑制剂的合成及初步活性测定

发布时间：2018-04-25 03:03

本文选题：氨基肽酶N + APN/CD13抑制剂　；参考：《南昌大学》2017年硕士论文

【摘要】：氨基肽酶N(APN)/CD13是一种多功能蛋白酶,存在于人体组织和细胞当中,具有多种多样的功能,与肿瘤的发生,免疫系统,疼痛等紧密相关。APN/CD13还可作为多种人类病毒的受体,如冠状病毒,以及参与抗原的修饰和抗原呈递等过程。实验表明在炎症性疾病和癌症(实体和血液肿瘤)中APN/CD13均过度表达,且研究已经证实APN/CD13参与了肿瘤发展的多个生理过程,如肿瘤血管的生成,侵袭以及肿瘤转移等,因此APN/CD13已经成为了研究新型抗肿瘤药物的重要方向。本课题依据APN/CD13的三维结构特点进行设计,引入类肽的设计理念,链接基团引入了丙氨酸和亮氨酸,在充分考虑本实验室活性研究结果的基础上,连接具有抗肿瘤活性的2-氨基-1,3,4-噻二唑结构以及活性中间体R-扁桃酸,结合计算机虚拟对接模拟技术,对结构进行优化,最终合成了具有抗APN/CD13活性的两个系列的二十三个新的化合物。对化合物进行初步的体外抑酶活性试验,筛选出9m和10j两个抑酶效果较好的化合物,其中9m为丙氨酸系列的化合物,10j为亮氨酸系列的化合物。从结果中我们可以发现当芳环被甲氧基取代时,抑酶作用最强,其次为硝基等其它的吸电子取代基,而供电子基团为取代基时,抑酶活性最低。利用计算机技术进行分子对接,得到的结果显示两个化合物均能够与氨肽酶N的催化锌离子发生螯合,而且化合物当中的多种原子可以与酶形成多个氢键,并与APN/CD13的疏水口袋的相互作用,加强了化合物与APN/CD13的相互作用。筛选出的两个活性较优的化合物可以作为先导化合物继续进一步的研究,该实验结果也可以作为依据用于继续改进优化化合物的基团和骨架,以便合成活性更好的化合物。
[Abstract]:Aminopeptidase N(APN)/CD13 is a multifunctional protease that exists in human tissues and cells. It has a variety of functions and is closely related to tumorigenesis, immune system, pain and so on. APN / CD13 can also be used as a receptor for many human viruses. Such as coronavirus, and participate in antigen modification and antigen presentation and other processes. The results show that APN/CD13 is overexpressed in inflammatory diseases and cancer (solid and blood tumors), and it has been proved that APN/CD13 is involved in many physiological processes of tumor development, such as angiogenesis, invasion and metastasis of tumor. Therefore, APN/CD13 has become an important direction in the study of new anti-tumor drugs. According to the three-dimensional structure characteristics of APN/CD13, this paper introduces the design idea of peptide like peptide, and the linked group introduces alanine and leucine, on the basis of fully considering the results of our laboratory activity research. The structure of 2-amino-1-tiadiazole with anti-tumor activity and the active intermediate R-mandelic acid were connected. The structure was optimized by computer virtual docking simulation technique. Finally, 23 new compounds of two series with anti-APN/CD13 activity were synthesized. The enzyme inhibition activity of the compounds in vitro was preliminarily tested. Two compounds, 9m and 10j, were screened out, among which 9m was alanine series and 10j was leucine. From the results we can find that when the aromatic ring is replaced by methoxy the inhibitory activity is the strongest followed by other electron-absorbing substituents such as nitro and so on while the inhibitory activity is the lowest when the donor group is the substituent. The results of molecular docking show that both compounds can chelate with zinc ion catalyzed by aminopeptidase N, and many atoms in the compounds can form multiple hydrogen bonds with the enzyme. The interaction with APN/CD13 hydrophobic pocket strengthens the interaction between compound and APN/CD13. The two compounds with better activity can be further studied as lead compounds. The results can also be used as the basis for further improvement of the groups and skeletons of the compounds in order to synthesize compounds with better activity.
【学位授予单位】：南昌大学
【学位级别】：硕士
【学位授予年份】：2017
【分类号】：R914

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