Process Research Of Tosedostat And Design, Synthesis And Preliminary Activity Study Of Novel Aminopeptidase N Inhibitors

Malignant tumor is one of the most serious disease threat to human health, and with the incidence rate and death rate rising continually in recent years, treatment of tumor has become a great challenge. Compelling evidence has identified that tumor cell can be killed by radiotherapy or chemotherapy, but unfortunately there is no radical treatment for tumor owing to its characteristics of relapse and metastasis. Subsequently, the discovery of cancer stem cells (CSCs), which is considered as the main reason for relapse and metastasis of the tumor, provides a new strategy for the treatment of tumor. To date, it has been identified that Aminopeptidase N (APN) is a cell surface marker of CSCs.APN, which is located on the surface of cells, is a zinc dependent membrane metalloprotease and belongs to M1 family. Furthermore, APN has been found to be highly expressed in various kinds of tissues and cells such as endothelial cell, hepatic cell, fibroblast and immunocyte. More recently, some studies have reported that APN is involved in numerous physiological processes such as signal transduction, angiogenesis, tumor invasion and proliferation. In addition, APN plays a essential role in immunity responses. Consequently, APN has received significant attention in recent years as therapeutic drug targets.Upon binding to the APN, the zinc binding group (ZBG) of a given inhibitor could chelate with the zinc in the catalytic domain of the APN and lead to the inhibition of catalytic activity, hence play an important role in biological function. There are two kinds of ZBG have been studied extensively:O-phenylenediamine and hydroxamic acid. Among them, hydroxamic acid has become the focus of our research due to hold a very strong chelating ability with zinc iron.Herein, we present our studies in two parts. In the first part, we modified the synthetic route of tosedostat, a clinical APN inhibitor. By literature study, we summarized two synthesis routes in previous reports, and then improved these two routes. After that, we optimized the conditions of synthetic reaction. With improvement, we could separate and purify intermediate and diastereoisomer in a simple way and receive optically pure compounds. In the second part, nine novel APN inhibitors, which were identified by NMR, were designed and synthesized. Then we study the preliminary biological activity for these new compounds. The result revealed that most compounds exhibited APN inhibitory, and that the compound DYZ, which is similar to bestatin in the inhibitory effect on APN, shows a better activity among these compounds.