Peptides C(sp~3)?H Arylation Directed By Natural Amino Acid

In recent years,peptide drugs have been a research focus in the pharmaceutical field due to their high target selectivity,stronger pharmacological activity and low toxicity.However,peptide drugs also have limitations,such as low bioavailability,poor membrane permeability and short half-life.Hence,researchers often use chemical methods to modify the structure of peptide drugs to improve their therapeutic effect.This paper focuses on a series of studies on natural amino acid directed C(sp~3)?H arylation.The first chapter reviews the application of late stage modification in peptide drugs and fluorescence chemosensors discovery.Extensive studies have shown that late stage modified peptide drugs could significantly improve their stability and bioavailability and reduce side effect.In addition,chemical modification could endow peptides with some excellent properties.The second chapter reviews the traditional reactions and C(sp~3)?H activation reactions applied to late stage modification of peptides.Traditional reactions have limitation of the type of substrates.However,C(sp~3)?H activation of peptides usually requires preinstallation and subsequent removal of directing group which reduce atom-and step-economy.Despite the advantage of using backbone as internal directing group,the C(sp~3)?H activation directed by backbone often lack of selectivity.Therefore,there is an urgent need to exploit novel internal directing group through C(sp~3)?H activation to modify peptides with high selectivity.The third chapter reviews the application of peptides containing phenylalanine-asparagine(Phe-Asn)sequence in the field of drugs discovery.Then,we design the peptides late stage C(sp~3)?H aryaltion assisted by unmodified side chain of Asn for the first time.Throughβ-C(sp~3)?H arylation of alanie at N-terminal peptides containing alanine-asparagine(Ala-Asn),the modified Phe is obtained,and peptides containing the modified Phe-Asn are further successfully constructed.After the screening of reaction conditions,the optimized protocols of C(sp~3)?H aryaltion of dipeptides,tripeptides and tetrapeptides are obtained.Simultaneously,various of amino acids and substituted iodoarene are used to test the generality of reaction.Fourteenarylated products of C(sp~3)?H bonds at N-terminus of dipeptides are synthesis with 56-73%yields,fifteen arylated products of C(sp~3)?H bonds at N-terminus of tripeptides are synthesis with 40-62%yields and sevenarylated products of C(sp~3)?H bonds at N-terminus of tetrapeptides are synthesis with 25-58%yields.To vigorously demonstrate that the side chain of Asn is indispensable in promoting the C?H activation process,control experiment and competition experiment are conducted.Additionally,through DFT calculations,the possible reaction mechanism is proposed.The fourth chapter reviews the research on the activity of AGRP and its analogues.Importantly,we have applied the C(sp~3)?H arylation directed by Asn to the synthesis of AGRP active loop analogues.Finally,two novel AGRP active loop analogues are obtained.The research provides a powerful reference for the synthesis of novel AGRP-based peptide drugs.