Synthesis And Activity Assay Of Alanine Hydroxamic Acid Aminopeptidase N Inhibitors

As a zinc ion-dependent type ? glycoprotein,aminopeptidase N is widely distributed on various cell membrances of mammals and in the central nervous system.As an exoprotease,aminopeptidase N is closely related to various diseases,is expressed in immune and central nervous systems such as arthritis,rheumatoid arthritis,gallstones,and Alzheimer's disease,is highly expressed in tumor cells such as human colon cancer,ovarian cancer,breast cancer,liver cancer.As an immune antigen involved in immunoregulatory process,viral infection process,inhibitor analgesia process,angiogenesis of tumor cells generation process,the growth,invasion and metastasis of tumor cells,etc.In combination with the specificity of the aminopeptidase N structure,these provide a theoretical basis for the synthesis of lead compounds.This study is based on the structural properties of aminopeptidase N on the design of the compound,due to the specificity and priority of its hydrolysis substrate.First select the alanine as a linking group,combined with the laboratory already based on the results of the active research,then choosing to connect cinnamic acid structure,benzoic acid structure,phenylacetic acid structure with good antitumor activity.Through the transformation of compound synthesis routes,the target compounds were synthesized by amidation,condensation,hydrolysis,mixed acid anhydride and other reactions.After confirmation by hydrogen spectroscopy,mass spectrometry and infrared spectroscopy,and consulted the related literature,the synthesis of 21 compounds are brand new compounds.In order to determine the inhibitory effect of target compound on human alveolar epithelial cancer cell A549,all new compounds are subjected to CCK-8 assay in vitro cell activity assay.The results show that 7a,9b,9c designed and synthesized in this project have good inhibition of lung cancer cell activity,all reach the micromolar level.By analyzing the structure of aminopeptidase N and the interaction between inhibitor and enzyme,computer design software is used to design molecular docking and synthesize peptidomimetic compounds.All the synthetic routes are convenient and concise,economical,safe and feasible.After screening by a preliminary in vitro cell viability assay,several novel active compounds of research valuable have been found,such as 7a,9b.The structure of the active compounds,their backbones,and the binding modes of their active targets are discussed,providing new ideas for designing and synthesizing compounds with better activity and higher selectivity.