Photoinduced Synthesis Of Isoindolone Bridged Cyclic Peptides And Bioactivity Study

At present,more and more peptide drugs have been developed and applied in clinical practice.Among natural active peptides,cyclic peptide drugs show more significant advantages.The cyclic backbone endows the cyclic peptides with unique conformational stability and can effectively resist enzymatic degradation and chemical degradation.However,the content of natural active cyclic peptides in organisms is relatively low,and extraction and separation are more difficult.Therefore,the total synthesis and structural modification of active cyclic peptides is an important direction for the development of cyclic peptides.Intramolecular light-induced single electron transfer reaction is an effective method for synthesizing cyclic peptides in line with the concept of green chemistry.Using phthalimide as electron acceptor and peptide chain as electron donor to form intramolecular donor acceptor system to prepare cyclopeptides by photo reaction will introduce isoindolone fragment,which is the main active structure of many antitumor small molecule compounds,and the introduction of isoindolone fragment will also increase the skeleton rigidity of cyclopeptides,increase the membrane permeability,increase the structural stability and reduce the conformation flexibility.Axinastatin 3 is a natural cycloheptapeptide with important antitumor activity extracted from sponges in the Western Pacific.In this study,phthalimide was used as electron acceptor and peptide chain was used as electron donor to form intramolecular donor acceptor system,after suitable light-induced excitation,Axinastatin 3 analogues were successfully synthesized through an intramolecular light-induced single electron transfer reaction.The stereoscopic structure of axinastatin 3 analogues was determined by electron circular dichroism(ECD)with theoretical calculation and the antitumor activity was studied by MTT method.It was found that compound 1a containing β-turn had strong antitumor activity.However,although compound 2a with theanine didn’t have good antitumor activity,there was a π-helix unit in the structure of compound 2a,which was rare,so it can be used as an important research object for the future study of unique helical secondary structure.The Phakellistatin family is a kind of proline-rich natural cyclic peptides isolated from natural sponges.Phakellistatin 18 and Phakellistatin 2 are cyclic hepteptides with the same amino acid residues and different sequences,which directly leads to a strong difference in biological activity.In this study,an intramolecular light-induced singleelectron transfer reaction was used to synthesize the analogues of Phakellistatin 18(compound 3a)and the analogues of Phakellistatin 2(compound 4a).With the help of theoretical calculations,the stereoscopic structure was determined by ECD.After the activity study by MTT method,the molecular docking with MDM2 protein was carried out by autodock tool.The results showed that compound 4a had stronger binding ability through hydrogen bonding,which provided an explanation for the difference of biological activity.In conclusion,this study used the intramolecular light-induced single electron transfer reaction to synthesize isoindolinone bridged cyclic peptides,and most of the synthesized peptidomimetic compounds have strong tumor growth inhibitory effects.In this paper,the main research on the effect of stereoscopic structure and activity is carried out.The established light-induced method and stereoscopic structure research program provide ideas for future antitumor cyclic peptide research.