| Peptide drugs have been widely used in the prevention,diagnosis and treatment of diseases due to their wide adaptability,high safety and significant curative effect,such as lilalutide,smeglutide and other drugs used to control blood sugar in adult T2DM(type 2 diabetes)patients.However,peptide drugs are easily hydrolyzed by peptidases and proteases,resulting in reduced bioavailability and poor pharmacokinetic characteristics,severely hampering their therapeutic potential.At present,a large number of experiments have proved that the introduction of unnatural amino acids or direct post-modification of polypeptide drugs can significantly reduce immunogenicity,reduce side effects,increase water solubility,prolong half-life,and change biodistribution.The cyano group is a common group in drug design.The introduction of cyano groups into drug molecules can regulate the physical and chemical properties of drugs,change the pharmacokinetics of drugs,and improve the bioavailability of drugs.Therefore,it is of great significance to introduce cyano groups into peptide drugs,and it also provides a new idea for the later functionalization of active biomolecules.This article will be expanded from the following two parts:The first part we summarized the drugs containing cyano groups and their pharmacological effects in recent decades.Secondly,we summarized the synthesis methods of unnatural amino acids containing cyano groups.We found that the current methods for synthesizing cyano-containing unnatural amino acids are very limited,especially the synthesis of cyano-containing chiral unnatural amino acids is more challenging.The second part introduces the synthesis of cyano-containing chiral unnatural amino acids and their application in chemical modification of polypeptides.In the previous work,our research group successfully realized the C(sp~3)-H alkylation reaction of glycine derivatives by using the visible light-induced copper-catalyzed asymmetric synthesis strategy,and synthesized a series of highly enantioselective unnaturalα-amino acids.On this basis,we used copper-catalyzed cyclobutanone oxime ester ring-opening reaction under the condition of no light to realize the effective coupling between glycine derivatives and cyclobutanone oxime ester,and synthesized a series of cyano-containing unnatural chiralα-amino acids,and successfully applied this method to polypeptide modification,provided a new solution for the later modification of polypeptide cyanoalkylation,and provided a new idea and method for the later functionalization of active biomolecules.At the same time,it also enriches the library of unnatural amino acids,providing a new solution for the design and synthesis of peptide drugs. |
