Novel Ester-Linked Carbohydrate−Peptide Adducts: Effect of the Peptide Substituent on the Pathways of Intramolecular Reactions

Abstract

Carbohydrate−peptide conjugates in which D-glucose is linked through an ester linkage to the carboxy group of Tyr-Pro (2), Tyr-Pro-Phe (5) or Tyr-Pro-Phe-Val (11), through the C6 hydroxy group of the sugar moiety were synthesized to examine the utility of this type of monosaccharide modification for peptide prodrugs. Evidence is provided that glycoconjugates 2, 5, and 11 easily undergo intramolecular chemical transformations, subsequent to attack of the free N-terminal amino group at the peptide backbone or at the anomeric position of the D-glucose moiety, resulting in the formation of diketopiperazine 12, glycosylamine 13, or keto-sugar derivative 15. The data indicated that the length and structure of the peptide chain are the main factors that control the intramolecular reactions of the carbohydrate−peptide esters studied.