Solid-phase synthesis of glucose-derived Amadori peptides.

Nonenzymatic glycosylation or glycation of amino groups in peptides and proteins by D-glucose is a universal reaction with important implications for the pathogenesis of many diseases including diabetes mellitus. Here a general approach is reported to synthesize site specifically glucose-derived N-glycated peptides. Therefore, model peptides H-AKASASFL-NH(2), H-AKASADFL-NH(2), H-ASKASKFL-NH(2), and H-AKDSASFL-NH(2) were synthesized on solid phase by Fmoc chemistry using Fmoc-Lys(4-methyltrityl)-OH in positions 2 or 3 to be glycated. After completion of the synthesis, the acid labile 4-methyltrityl-group was cleaved with 1% TFA in DCM and the free amino groups were glycated by the Lobry de Bruyn reaction using 2,3:4,5-di-O-isopropylidene-aldehydo-beta-D-arabino-hexos-2-ulo-2,6-pyranose on solid phase. After TFA treatment, the crude peptides were obtained in high yields and purities above 80%. Minor by-products were well separated on reversed-phase HPLC.