Chemical Synthesis Of Peptides And Their Derivatives

This thesis consists of two projects that belong to the field of peptide chemical synthesis.In the first project, a new method has been established to synthesis peptide thioesters, a type of key intermediates used for the chemical synthesis of proteins in native chemical ligation technology. The established method has the following features: keep the advantages of Fmoc solid-phase peptide synthesis (SPPS) technology but avoid its weakness of thioesters aminolysed during SPPS; use allyl as the C-terminal protecting group in the peptide chain to make the thioester formation possible under Fmoc SPPS; provide an efficient way to connect the side chain functional group of the C-terminal amino acid to the resin through special linkers. 15 products that contain lysine, aspartic acid and glutamic acid as the C-terminal amino acid of the peptide chain have been synthesized successfully using the method, in which include a long chain peptide thioester with 33 amino acids. The established method will become a useful tool in the protein chemical synthesis field.The second project concentrates on the research and exploring efficient methods for the synthesis of the FK228 analogues, a type of peptide derivatives with anticancer activity through special mechanisms. In this project, various amino acid derivatives are synthesized and used as the building blocks in the FK228 analogues; a series of peptide segments including dipeptide, tripeptide, tetrapeptide and pentapeptide derivatives are prepared as the intermediates of the target compounds; special coupling reagent HOCt is applied for the peptide bond formation to improve the synthesis efficiency; an efficient method is established to form intramolecular disulfide bond selectively and avoid intermolecular side reaction; totally 46 compounds are synthesized to support the syntheses of the target products; and one synthetic cyclic peptide analogue with intramolecular disulfide bond shows the inhibiting activity to the MCF-7 cell proliferation in cell experiment. The results obtained in this project will be very important for the further research on the synthesis of FK228 analogues, and will be helpful to the research and development of new antitumor drugs.