Diverse Synthesis And Application Of Azapeptides Based On Mitsunobu Reaction

Azapeptides are peptide analogs that contain one or more aza-amino acids in the peptide skeleton.The ?-carbon atom in the aza amino acid is replaced by a nitrogen atom,resulting in a semicarbazide structure.Due to the planarity of the urea structural unit and the repulsion between the lone pairs of electrons on the two nitrogen atoms in the hydrazine structural unit,the aza structural unit has a strong rigidity and is more likely to induce the peptide backbone to form a ?-turn structure.Azapeptides exhibit enhanced protease stability,as well as enhanced target selectivity and affinity.Thus it is now widely used as a peptide analog for enzyme inhibitors,ligands for specific receptors,and bioactive probes.In this paper,we investigated the diversification of the aza structural units by constructing and modifying peptides via new synthetic methods and applied these methods to the synthesis of the bioactive peptide Ang-(1-7).Preliminary activity evaluation of Ang-(1-7)and its aza derivatives is expected to further advance the use of azapeptides in drug discovery.Therefore,this thesis focuses on the development of methodologies for the synthesis of diverse azapeptides and the study of the activity of Ang-(1-7)analogues.The first chapter of the thesis summarizes the research background of this topic from the following aspects: the current status of research on peptides and their analogues,the structural analysis and synthesis methods of azapeptides,the synthesis and application of Freidinger-Veber lactamides and their derivatives,the development of the Mitsunobu reaction,and the renin-angiotensin system.The second chapter of the thesis focuses on the submonomer method for the regioselective alkylation of azaglycine under alkaline conditions in the diverse synthesis of azapeptides,which may result in racemization and hydrolysis.We have successfully developed an intermediate for azapeptide synthesis by introducing 2-nitrobenzylidene protected azaglycine residues,and regioselective alkylation by mild Mitsunobu reaction to avoid the use of strong bases.This method can introduce aza amino acid side chains through different alcohols,which can be applied to the synthesis of diverse azapeptides,and further widely used in solid-phase azapeptide synthesis.Based on this method,we successfully applied it to the synthesis of a series of Aza-Ang-(1-7)analogues,providing a basis for subsequent studies to develop Aza-Ang-(1-7)analogues for drug discovery.The third chapter of the thesis focuses on a class of peptides containing a novel N-aminoimidazolidin-2-one(Aid)structural unit by the further introduction of side-chain hydroxylated amino acids(serine)into the peptides and the cyclization by intra-molecular Mitsunobu reaction.Based on this method,we successfully synthesized a series of AidAng-(1-7)analogues,providing the basis for subsequent studies to develop Aid-Ang-(1-7)analogues for drug discovery.The fourth chapter of the thesis focuses on the preliminary evaluation of the anticancer and anti-inflammatory activities of a series of Aza-Ang-(1-7)and Aid-Ang-(1-7)analogues synthesized by the above-mentioned methods.The results suggested that the analogues of Aid-Ang-(1-7)hold potential in anti-inflammatory effects and might be developed into anti-inflammatory drugs through further studies.In summary,in this thesis,we have successfully developed a method for the diversified synthesis of azapeptides based on the Mitsunobu reaction by introducing a 2-nitrobenzylidene-protective group,and further we have successfully synthesized a class of structurally novel Aid peptides by the intramolecular Mitsunobu reaction.Furthermore,we successfully synthesized a series of Aza-Ang-(1-7)and Aid-Ang-(1-7)analogues by using Ang(1-7)as a template.A preliminary bioactivity screen of the synthesized azaanalogues revealed that Aid-Ang-(1-7)held potential anti-inflammatory effects.Therefore,we developed a new method for the synthesis of azapeptides and successfully applied it to the synthesis of Ang-(1-7)analogues to advance the application of azapeptides in the field of drug discovery.