Study On Solid Phase Synthesis Methods Of Azapeptide And Its Application

As a class of peptide analogs,azapeptides have been widely used in the field of drug research,including as enzyme inhibitors,ligands for specific receptors,and biological probes.Due to their unique advantages in conformational and structural diversification,azapeptide often exhibits enhanced stability and affinity.The introduction of non-natural aza-residues in the peptide chain is also a very practical tool for studying the structure-activity relationship of bioactive peptides and for peptide stability studies.In this thesis,we mainly study how to construct and modify the aza structural units in peptides,and apply these methods to the synthesis of bioactive peptide analogs.It is expected to find lead compounds with medicinal value and promote the development of azapeptide drugs.This research focuses on two aspects of the solid phase synthesis of azapeptides.The first is to establish protocols for introducing and modifying the structure of aza-residues in peptide,and the second is to study the application of the protocol in the synthesis of biologically active peptide analogs.In the first part of this subject,we explored a method for synthesizing a new class of bicyclic azapeptides,which utilizes A~3-Coupling reaction between two terminal alkyne-functionalized aza-residues and an amino group of lysine side chain in the peptide chain.The exploration for the synthesis of bicyclic azapeptide structure,unfortunately,was unsuccessful due to the challenging bicyclic structure and other various factors.In the second part of the project,a new protocol for azaproline synthesis was designed by alkylation of the?-NH group of aza-glycine.Employing the newly developed submonomer synthesis of azapeptide,we first successfully introduced a hydroxypropyl side chain at the azaglycine residue,followed by an intramolecular Mitsunobu reaction for alklation?-NH group of aza-residue affording the desired azaproline unit,and this method is successfully applied to the synthesis of angiotensin II analogs.In the third part of the project,the post-modification of azapeptide precursor with an azaalanine moiety was carried out,utilizing the Mitsunobu reaction for alkylation of the?-NH of the azaalanine.This method could be a general route for synthesizing?-N-methyl azapeptoid analogs.Employing this protocol,a series of azapeptoid derivatives of angiotensin 1-7 were synthesized.This research,we explored the synthesis of novel bicyclic azapeptides,successfully developed a new protocol for the formation of azaproline,and finally developed a new strategy for diversity-oriented synthesis of?-N-methyl azapeptoid.An azaproline containing Angiotensin II analog and a series of azapeptide analogs of angiotensin 1-7 were synthesized using the newly developed azapeptide synthesis method.This thesis is of great significance for exploring new synthetic routes of azapeptides and diversification of aza-peptide analogues,and builds up a solid foundation for further promoting the discovery and development of azapeptide drugs.