A Novel Stabilized Conformational Restriction In N-Oxidized Peptides(NOP)

At this stage,biologically active peptides have become hot-spotting compounds for pharmacists looking for new drugs.Its outstanding advantages are low toxicities and side effects,but its development process is also limited by its own characteristics.Because peptide compounds are formed by amino acids and also exposed to various proteases in the body environment.Therefore,it has a short half-life because it is prone to degradation,and it is also not suitable for the development of oral preparations.Another constraint is poor cell permeability,which hinders transmembrane transport.Therefore,how to develop long-lived and effective peptide drugs in the invivo environment is a difficult task in this field.At present,breakthroughs have been made in improving the receptor selectivity of peptide drugs.The main problems faced in the study are the short half-life in vivo,the difficulty in effective binding with targets,and the inability to function.Because proteases are present in many parts of the body's internal environment,they participate in biochemical reactions at various stages.Therefore,the risk of peptide drugs being degraded is relatively large,resulting in the influence of various parameters of the pharmacokinetics of the drug.The key to the development of bioactive peptides as drugs is the degree of degradation by proteases.The stability is the core of the effectiveness of these drugs.Conformational restriction is one of the important means to overcome peptide defects.This dissertation mainly summarizes the conformational restriction of the novel peptides containing N-oxides(NOP),including the molecular design and multistep synthesis of peptidomimetics,and the identification of secondary structures.The paper has four chapters.Firstly,this topic summarizes the existing conformational restriction research strategies and methods of peptidomimetics.These include the conformational restriction methods of alph-peptides and beta-peptides and summarize the classical methods for the identification of peptide space structures.Through literature research and pre-experimental analysis,we firstly introduced the N-oxide as a functional group for the study of the conformational strategy of novel peptides.The design ideas of this topic were summarized in this paper.We firstly validated our strategy through four NOPs,and a series of peptidomimetics were synthesized to further verify our ideas using the classical peptide condensation method and tertiary amine oxidation method.The NOPs models were established through continuous trials and empirical summaries during the synthesis process.Finally,spatial structure identification of all novel peptides with definite chemical structure was performed,including:NMR and NOE spectra datas,infrared datas,crystal datas,circular dichroism datas,and computer simulation datas.A detailed analysis of the hydrogen bond changes and formation in peptide molecules was performed to determine the secondary structure of the NOPs.We conclude that the NOPs have novel conformations,N-oxide has strong nucleophilic properties to form hydrogen bonds with adjacent amide hydrogen atom and constitutes a localized circular conformation.Therefore,it can serve as an effective peptide conformation restricted tool.