Synthesis of tripeptides for chelating metals involved in the aggregation of the ß-amyloid peptide responsible for Alzheimer disease

Abstract

This work has been done in collaboration with the Bioinorganic Chemistry group of Inorganic Chemistry Department. This group is interested in chelating oligopeptides (about 3 or 4 amino acids) for metal ions such as copper and zinc, potential theranostic agents for Alzheimer disease. 1 Thereby we have synthesized peptides that contain at least two histidine residues (as metal-binding groups) and one natural or non-natural fluorescent amino acid (for detection purposes). We have used as fluorescent amino acids: tryptophan (W), tyrosine (T) and the non-natural amino acid Nε-(coumarin-3-ylcarbonyl)-L-Lysine (K(C)). The latter has been prepared in solution by reaction of 1H-benzotriazole with 2-oxo-2H-chromene-3-carboxylic acid to yield 3-(1Hbenzotriazol- 1-ylcarbonyl)-2H-chromen-2-one (52-60%) and the subsequent transformation of this intermediate to the final product by reaction with Fmoc-L-Lys-OH under basic condition (60- 85% yield). It has been characterized by proton nuclear magnetic resonance (1H-NMR). The synthesized peptides have been: histidine-alanine-histidine (HAH), histidine-alaninehistidine- tyrosine (HAHY), histidine-histidine-tryptophan (HHW), histidine-lysine(coumarin)- histidine (HK(C)H) and histidine-tryptophan-histidine (HWH) (Figure 1). HAH is the only one that hasn’t any fluorophore, but it has used as a blank to determine if fluorescent amino acid chelates the metal...