Synthesis And Applications Of Aza-peptoid Based On Mitsunobu Reaction

Angiotensin-(1-7)plays an important role in organisms which has lots of physiological effects such as regulating blood pressure,inhibiting cell proliferation,protecting cardiovascular,as well as anti-fibrosis,anti-inflammatory,therefore,Ang-(1-7)is considered to be an ideal drug for the treatment of diseases.However,the biological half-life of Ang-(1-7)is short,it is easily hydrolyzed by enzymes into peptides with no biological activity,which limites its clinical application.For this reason,in this study,chemical modification methods are used to synthesize and discover Ang-(1-7)aza peptoids with good protease stability.Azapolypeptides are polypeptide mimics containing one or more aza-amino acids.Compared with natural polypeptides,α-C atoms in aza peptides are replaced with N atoms,so the long pair of aza-peptides α-N atom and carbonyl oxygen atom has a repulsive effect on electrons,which can effectively induce the polypeptide structure to form β-turn structure.At the same time,the introduction of aza units can improve the metabolic stability and affinity with the target.Based on this,aza peptoides have great potential for development in drug applications.Rencently,our research group used the Mitsunobu reaction to successfully develop an effective new method for the synthesis of aza-peptides.In order to further expand the diversity of aza-peptides,in this study,we try to use the Mitsunobu reation to synthesize a new type of azapeptides analogues: aza peptoids which has a diverse alkyl side chain of the β position of the aza amino acid residue.This article focuses on two aspeccts of the synthesis method and application of azapeptoids.1)Fmoc-protected methyl-hydrazine was constructed on the liquid phase as the precursor of azaalanine.Using peptide solid-phase synthesis method,azaalanine was introduced into different positions of Ang-(1-7),and a series of Ang-(1-7)analogues containing azaalanine structure were obtained.Because of the relatively strong acidity of the NH group at the β-position of heteroalanine residues,we can utilize Mitsunobu reaction to carry out regioselective alkylation reaction,introducing different side chains on β amino group,by doing this,we can successfully construct a series of Ang-(1-7)α-N methyl aza-peptidomimetic analogs.2)Based on the successful synthesis of the above-mentioned azapeptide,by sequentially replacing the two adjacent amino acids of Ang-(1-7)with the dipeptide units of serine and azaalanine,using the intramolecular Mitsunobu cyclization reaction,The NH group at the β position of azaalanine undergoes intramolecular alkylation with the hydroxymethyl group of the side chain of serine to form a 1,2,4-triazin-3-one structure.Using the solid-phase synthesis method,a series of Ang-(1-7)azapeptide analogs containing 1,2,4-triazin-3-one structure are obtained.In summary,using aza-alanine as the precursor structural unit of the aza-peptide,we successfully developed a synthetic method for the α-N-methyl aza-peptoids and successfully applied it to synthesize a series of aza-peptoid Angiotensin-(1-7)analogs.Furthermore,based on this method,we successfully used the intramolecular Mitsunobu cyclization reaction to successfully synthesize a series of aza Angiotensin-(1-7)analogs containing 1,2,4-triazin-3-one structure.It laid the foundation for the subsequent discovery of the aza-peptidomimetic analogues of Angiotensin-(1-7)with good protease stability.At the same time,the research and development of azapeptide synthesis methods have broad application prospects in the synthesis of azapeptide analogs of other biologically active peptides,and laid a foundation of azapeptide-based drug discovery.