Abstract
Pathological levels of oxidative stress (OS) have been implicated in many diseases including diabetes mellitus, neurodegenerative diseases, inflammatory diseases, atherosclerosis, and cancer. Studies of oxidative stress are however complicated by the low concentration of oxidation products. To resolve this problem, we tested a new derivative of aminoadipic semialdehyde (Fmoc-Aea-OH) in the solid-phase synthesis of carbonylated peptides. We prepared a series of peptides with free and acetylated N-terminal amino groups using the Fmoc-Aea-OH reagent. LC-MS, ESI-MS, and MS/MS spectra confirmed the sequences of the modified peptides, although the LC-MS and ESI-MS spectra were dominated by signals corresponding to dehydration products. NMR studies of acetylated products revealed that the dominant product formed in this reaction contains a 1,2,3,4-tetrahydropyridine-2-carboxylic acid residue. Another side reaction in this system was the cleavage of the amide bond between the Aea residue and the amino acid moiety preceding it resulting in the formation of a side product with a six-membered ring at the N-terminus (2,3,4,5-tetrahydropyridine-2-carboxylic acid residue). We found that, depending on the peptide sequence, one of those side products is predominant. Our work suggests new methods for the solid-state synthesis of peptides containing unnatural amino acids.
Highlights
Pathological levels of oxidative stress (OS) have been implicated in a plethora of diseases ranging from diabetes mellitus and neurodegenerative diseases to inflammatory diseases, atherosclerosis, and cancer[1,2,3]
We investigated the use of an unnatural, commercially available derivative of aminoadipic semialdehyde (Fmoc-Aea-OH) as a building block in the solid-phase synthesis of modified peptides
One of major products contained a 1,2,3,4-tetrahydropyridine-2-carboxylic acid residue formed by interaction of the protonated aldehyde group with the amide bond; the other contained the N-terminal 2,3,4,5-tetra hydropyridine-2-carboxylic acid residue resulting from cleavage of the peptide bond adjacent to the Aea residue
Summary
Pathological levels of oxidative stress (OS) have been implicated in a plethora of diseases ranging from diabetes mellitus and neurodegenerative diseases to inflammatory diseases, atherosclerosis, and cancer[1,2,3]. We performed the synthesis of carbonylated and glycated model peptides on a solid support using designed and synthesised building blocks[13,14]. The first pathway uses conventional synthetic methods to yield the reduced form of allysine, 2-amino-6-hydroxyhexanoic acid This compound is oxidized to the allysine derivative after introducing the protective groups at the amino- and carboxyterminus. We used a commercially available derivative of aminoadipic semialdehyde, Fmoc-Aea-OH (Fmoc-L-allysine ethylene acetal), containing the oxidative modification occurring in living organisms, in the solid-phase synthesis of carbonylated peptides. We checked the reactivity of the aldehyde group in the peptide sequence to determine the influence of different amino acid residues on the formation of the desired carbonylated peptide. Our work suggests new methods for the solid-state synthesis of peptides containing unnatural amino acids
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