Synthesis and inhibitory activity of substrate-analog fructosyl peptide oxidase inhibitors.

Fructosyl peptide oxidases (FPOXs) play a crucial role in the diagnosis of diabetes. Their main function is to cleave fructosyl amino acids or fructosyl peptides into glucosone and the corresponding amino acids/dipeptides. In this study, the substrate-analog FPOX inhibitors 1a–c were successfully designed and synthesized. These inhibitors mimic Nα-fructosyl-l-valine (Fru-Val), [Nα-fructosyl-l-valyl]-l-histidine (Fru-ValHis), and Nε-fructosyl-l-lysine (εFru-Lys), respectively. The secondary nitrogen atom in the natural substrates, linking fructose and amino acid or dipeptide moieties, was substituted in 1a–c with a sulfur atom to avoid enzymatic cleavage. Kinetic studies revealed that 1a–c act as competitive inhibitors against an FPOX obtained from Coniochaeta sp., and Ki values of 11.1, 66.8, and 782μM were obtained for 1a–c, respectively.