The Synthesis And Preliminary Activity Study In Vitro Of Low Molecular Weight Peptidomimetic Derivatives As APN Inhibitors

AminopeptidaseN(APN, as known as CD13)belongs to a family of zinc-dependent type Ⅱmetalloproteinase, is widely distributed in many tissues of mammalian such as: kidney, intestine, liver as well as central nervous system. As an exopeptidase, APN is involved in the degradation extracellular matrix, so it play crucial roles in many physiological processes. Furthermore, APN also a receptor for corona viruses, and it is involved in the trimming of antigen and the process of antigen presentation. APN is highly expressed in many tumor cells, and plays an pivotal role in tumor invasion, metastasis and angiogenesis. As the enzyme has close relationship with the some cancers and viruses, more and more researches focus on the field which require the development of potent and more selective inhibitors.In this thesis, based on the APN as the target, the three dimensional crystal structure of enzyme and the known structure of peptide-like derivatives as APN inhibitors, the previous work of our lab, used the computer-aided drug design software,we design and synthesize two series of 21 low molecular weight peptide-like derivatives: propagandize compounds and leucinamide compounds. The target compounds are prepared by the reaction of substitution, acylation,esterification.Their structures are confirmed by IR, 1H NMR and ESI-MS. All of them are novel without any report by now.Preliminary bioactivity(APN) assays are carried out in vitro. The experimental results shows these new compounds have potent and selective inhibitory activities toward APN with IC50 values in the micromolar range.Based on the binding characteristics learned from the latest three dimensional crystal structure of APN and virtual screening, peptide-like derivatives of APN inhibitors were designed and synthesized. These new compounds showed good APN inhibitory effect.We reported a convenient and economical method of the synthesis of APN inhibitors. The most potential compounds, such as 7e, 8e. We also established a QASR model of the target compounds, which is beneficial for the novel APNinhibitors in the future.