Oxidative Construction Of Disulfide Bonds In Peptides By Pt(?) Complex

In recent years,peptide-based drugs have been widely used in clinic because of their low toxicity and easy synthesis.Among them,many drugs contain intramolecular disulfide bonds.Disulfide bonds plays an important role in maintaining a peptide's secondary structure and increasing its specificity to the target molecule.As a result,the drug activity enhanced accordingly.Therefore,to synthesie intramolecular disulfide bond in an efficient and high-yield manner is a hot spot in the research of peptide drugs.In this work,trans-[Pt?OH?₂?phen??en?]²⁺was synthesized and characterized by Elemental analysis?¹H NMR and ESI-MS.The reactions between reduced pressinoic acid and trans-[Pt?OH?₂?phen??en?]²⁺were investigated in various solutions.Better yield and shorter reaction time were achieved when the reaction was carried out in HBr solution.Moreover,Other nine reduced peptides were reacted with the platinum???complex in the HBr solution.The yields were almost reached 100%,and no side reactions occurred on the methionine,tyrosine and tryptophan residues.Finally,a reaction mechanism for the reaction of trans-[Pt?OH?₂?phen??en?]²⁺with reduced peptide in HBr solution was proposed.The reaction between a platinum???prodrug model complex trans-[PtCl₂?CN?₄]^2-and a peptide containing cysteine and methionine groups was studied by HPLC and ESI-MS.The two cysteines in the peptide were oxidized to an intramolecular disulfide bond,while thioether of methionine was oxidized to its sulfoxide derivative.A novel intermediate was observed and characterized by ESI-MS,and then generated methionine sulfoxide derivate through a redox reaction.The intermediate was formed through substitution of a axial chloride ligand of the platinum???complex by the sulfur atom of the methionine residue.Accordingly,an oxidiation mechanism was proposed for the redox reaction.When ormaplatin and cis-[Pt?NH₃?₂Cl₄]react with this peptide,two cysteines were oxidized to an intramolecular disulfide bond,while thioether of methionine was intact.