Synthesis And Application Of Cyclic Azapeptides

Peptides are a class of natural molecules with unique biological activities and are important sources of drug discovery.Peptide drugs have unique advantages: broad bioactivity,high target selectivity,strong specificity,weak systemic toxicity,and difficulty accumulating in the body.However,due to the inherent shortcomings of the peptides in pharmacokinetics,such as poor biostability,short half-life,poor membrane permeability,and low bioavailability,the use of peptides in drug discovery is hampered.How to improve the stability of peptides by chemical modifications,improving their affinity and bioavailability are important challenges in the development of peptide drugs.The cyclic peptide plays an important role in the discovery of peptide drugs.By forming a cyclic structure,the biological stability and target selectivity of the peptide molecule can be improved,as well as the bioavailability is improved.Azapeptides are a class of peptide analogs containing one or more aza-amino acids,by substituting the α-carbon of the amino acid with a nitrogen atom,the aza-amino acid has a structural unit of a semicarbazide,which enhances its biostability.Due to the increased biostability of azapeptides for protease degradation,azapeptides are a class of peptide analogs that have broad applications in drug discovery.Based on the advantages of two types of peptide analogs,cyclic peptides and azapeptides,we intend to explore the synthesis and application of aza-cyclopeptide.In this thesis,we first explored to develop a new synthetic protocol of aza-cyclopeptide,and then employing the protocol for synthesizing aza-cyclopeptide molecules with good biological activity and we hope to find drug molecules with promising applications.The first part of this thesis is to explore the synthesis of aza-cyclotetrapeptide.It is suggested that the use of aza-amino acids may induce β-turn conformation,therefore,we can utilize this characteristics to promote the synthesis of small cyclic peptides with rigid structures.By selecting a natural cyclic tetrapeptide Cyclo-[Pro-Tyr-Pro-Val],a tyrosinase inhibitor as a template,the synthetic protocol of rigid aza-cyclotetrapeptide with conformational constraint was explored to verify whether introducing an aza-residue could overcome the problem of cyclization of small cyclopeptides.In the other hand,by applying the method to the synthesis of a series of aza-cyclotetrapeptide,it is expected to find a drug-forming aza-cyclotetrapeptide.In the second part of this thesis,the stapled azapeptide was explored.By combining the structural advantages of azapeptide and staple peptide,we expect to find a novel strategy for the application of azapeptide in drug discovery.The active peptide PDI with dual inhibitory effect on p53-MDM2/MDMX interaction is used as a template and a series of aza-stapled analogs was designed and synthesized.Through systematic studies of the synthesis and activity screening of azapeptide analogs,the structural activity relationship of aza-staple peptides can be established.This could be an new route for azapeptide drug development.The research in this thesis combines the chemical modification strategies used for peptide mimics,namely azapeptides and cyclic peptides,which provides a new concept for the research and development of peptide drugs,and hopes to promote the research and application of azapeptides in drug discovery.