The Synthesis And Preliminary Activity Assay In Vitro Of Low Molecular Weight Peptide-like Derivatives As APN Inhibitors

AminopeptidaseN(APN)belongs to a family of zinc-dependent metalloproteinase that plays an essential role in tumor invasion and angiogenesis. APN is involved in the degradation of ECM and facilitates the growth and metastatic spread of tumors. In addition, APN also serves as a receptor for corona viruses, and it is involved in the trimming of antigen and the process of antigen presentation. All these findings make this enzyme an interesting target for possible anti-tumor drugs research, which require the development of potent and more selective inhibitors.In this thesis, based on the known structure of peptide-like derivatives as APN inhibitors, crystal structure of the enzyme and application of computer-aided drug design software, we design and synthesize two series of 14 novel peptide-like derivatives: phenylacetyl derivatives and benzenesuifonyl derivatives. The target compounds are prepared by the reaction of substitution, esterification, acylation, condensation. Their structures are confirmed by IR, ESI-MS, 1H NMR and 13C NMR.Preliminary bioactivity assays are carried out in vitro. The target compounds are evaluated for inhibitory activities toward APN and MMP-2. Both the APN and MMP-2 which have two Zn2+ in the active site belong to a family of zinc-dependent metalloproteinase, so the APN inhibitors would display inhibitory activities on MMP. As a result, most of these newly synthesized compounds show good inhibitory activities on APN. Data of the comparative studies exhibits the selectivity towards APN is higher than towards MMP-2. These new compounds have potent and selective inhibitory activities toward APN with IC50 values in the micromolar range.In this thesis, we try to design the peptide-like derivatives that have good inhibitory activities on APN in vitro. Some of these compounds, such as 1g, 2g, which could conformationally match the requirement of the active site of APN, are supposed to have good anti-tumor activity in vivo.