Protocol for efficient solid-phase synthesis of peptides containing 1-hydroxypyridine-2-one (1,2-HOPO)

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Coordination Chemistry

Background:

• Metal chelation is crucial for human health, with natural siderophores being potent Fe(III) chelators.
• 1-Hydroxypyridine-2-one (1,2-HOPO) moieties mimic natural siderophores and are key components in synthetic chelators.
• Previous synthesis of 1,2-HOPO chelators involved harsh deprotection steps for the N-OH group.

Purpose of the Study:

• To develop a more efficient method for incorporating 1,2-HOPO-4-carboxylic acid into peptide backbones.
• To establish a milder deprotection strategy for the benzyl (Bzl) protecting group on the 1,2-HOPO N-OH moiety.
• To facilitate the synthesis of novel 1,2-HOPO-based metal chelators.

Main Methods:

• Solid-phase synthesis of peptides incorporating 1,2-HOPO-4-carboxylic acid without N-OH protection.
• Development of a simultaneous deprotection and cleavage method using trifluoroacetic acid-trifluoromethanesulfonic acid-water (TFA-TFMSA-H2O).
• Comparison of the new methods with existing harsh deprotection protocols.

Main Results:

• Successful incorporation of 1,2-HOPO-4-carboxylic acid via its carboxyl group without N-OH protection.
• A milder, concomitant deprotection of the Bzl group during global deprotection and peptide cleavage.
• Avoidance of harsh reagents like BBr3 or HBr, simplifying the synthetic process.

Conclusions:

• The proposed methods offer a more facile and efficient route for synthesizing 1,2-HOPO-containing chelators.
• These advancements can broaden the application of 1,2-HOPO chelators in various fields, including medicine.
• The optimized synthesis contributes to the development of new therapeutic and diagnostic agents.