Synthesis And Conformational Analysis Of N-methylated Peptides Containing Dehydrophenylalanine Or Dehydroalanine Residue

Peptide drugs have been widely used in the field of disease treatment due to their strong biological activity and specific proterties,such as the treatments of metabolic diseases,cancer,and autoimmune diseases.However,polypeptide compounds also have drug-making disadvantages.Firstly,because of poor stability of polypeptide molecules,they are easily to be degraded by various peptidases;Secondly,it has poor cell membrane permeability due to large molecular weight;Finally,intrinsic flexibility of peptides show that it could be recognized by a variety of receptors in different conformations,which may lead to many adverse reactions.In order to overcome the common shortcomings of polypeptides,various methods are applied to modify the structure of the polypeptides.The introduction of dehydroamino acids into the polypeptide structure is an important way of modifying the structure of the polypeptide,which can form a rigid structure,increase the enzyme resistance,and improve the biological activity of the polypeptide.N-methylation of polypeptide amide bonds is also an important method to improve the biological activity of polypeptides.The introduction of dehydroamino acids into peptides requires knowledge of the conformational properties of the dehydroamino acid residues.In order to study the effects of N-methylation of C-terminal amide groups on the conformational properties of ?,?-dehydropeptides,five model peptides Boc-?Ala-NH-pCl Boc-?Ala-Gly-NH-pCl,Boc-?Ala-Gly-N(Me)-pCl,Boc-(Z)-?Phe-Gly-NHMe and Boc-(Z)-?Phe-Gly-NMe2 were designed and synthesized in this thesis.The conformation of the compound in CDCl3 was analyzed by NMR method and the solid-state conformation of Boc-(Z)-?Phe-Gly-NHMe was analyzed by X-ray diffraction.The theoretical calculations of the DFT(B3LYP)level using the Gaussian 09 quantum chemistry package support the experimental results.The final result showed that the 1?4 hydrogen bond is essential for stabilizing the dipeptide containing ?Ala or(Z)-?Phe residues at the i+1 position to form ?,?-turn structure.Therefore,the tendency of N-methylated Boc-?Ala-Gly-N(Me)-pCl and Boc-(Z)-?Phe-Gly-NMe2 to form ?-turn structures is correspondingly higher than the corresponding unmethylated peptides Boc-?Ala-Gly-NH-pCl and Boc-(Z)-?Phe-Gly-NHMe were stronger.