Synthesis Of Azacyclopeptide Analogues Of ANG(1-7)

More than 7000 naturally occurring peptides have been identified,and these often have crucial roles in human physiology,including actions as hormones,neurotransmitters,growth factors,ion channel ligands,or anti-infectives.Because it has pharmacological properties such as good safety and excellent target selectivity,peptide-based drug design and modification has become a new focus.Compared with traditional small molecules,peptides have excellent safety,tolerability,and efficacy profiles.Furthermore,peptide therapeutics are typically associated with lower production complexity compared with protein-based biopharmaceuticals and,therefore,the production costs are also lower,generally approaching those of small molecules.Thus,in several ways,peptides are in the sweet spot between small molecules and biopharmaceuticals have great potential in drug development.However,peptides as natural products often need to overcome the shortcomings of poor moldability,low bioavailability,and poor protease stability in the development of drugs.Therefore,in order to improve the undesirable properties of the peptide so that it can be used clinically,it is urgent to optimize and modify the structure of the peptide.An azapeptide,as a peptidomimetic,is formed by replacing one or more α-carbon atoms of a polypeptide with a nitrogen atom.Such azapeptides not only have a more stable semicarbazide structure,but also make the peptide structure tend to a stableβ-turn structure.These structural changes will make azapeptides have higher protease stability and receptor affinity.Therefore,azapeptides are used in enzyme inhibitors,specific receptor ligands,bioactive probes,and pharmaceutical research widely used cyclic peptides are well known as natural products.The cyclic conformational restriction brings higher stability,selectivity,and membrane permeability to cyclic peptides.In addition to the discovery of a large number of natural cyclic peptides,currently the number of synthetic cyclic peptides is also increasing,so that the proportion of cyclic peptide drugs has reached 3% of peptide drugs.However,there are few studies on azacyclopeptide.Restriction of azapeptides by cyclization will make their β-turn structure more stable.It combines the advantages of cyclic peptides and aza peptides,making the peptides have better enzyme stability and better affinity for receptors.It has great potential in drug research.In this study,Fmoc methylhydrazine was first synthesized in the liquid phase,and then it was coupled to an amino acid-containing resin by BTC to form an acid chloride.Furthermore,serine was introduced,and the presence of methyl groups on α-N in azaalanine increased the acidity of β-N-H to promote the Mitsunobu reaction in the molecule.Intramolecular Mitsunobu ring formation was successfully completed by N-H of azaalanine and OH on serine.Based on the successful synthesis of the aza six-membered cyclic peptide,its synthetic method was also optimized.Subsequently,this article provides the idea of aza nine-membered ring synthesis.Finally,this method was applied to the natural active peptide ANG(1-7).After optimizing its synthetic route and method,it successfully constructed an aza six-membered cyclic compound library.In summary,this study uses the Mitsunobu reaction with mild reaction conditions.After continuous optimization of the conditions,the synthesis of azacyclopeptides has become simpler and more efficient,which is of great significance for the development of biologically active peptides in the future.The establishment of the azacyclopeptide library has also laid a good foundation for the development of peptide drugs in the future.