Convergent Synthesis of Thioether Containing Peptides

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Biochemistry

Background:

• Thioether-containing peptides are valuable in drug discovery and chemical biology.
• Efficient synthesis of these peptides is crucial for expanding their applications.
• Existing synthetic methods may have limitations in scope or efficiency.

Purpose of the Study:

• To develop and compare three distinct synthetic routes for thioether-containing peptides.
• To establish versatile methods for incorporating thioether linkages into peptide structures.
• To generate novel peptide building blocks for solid-phase peptide synthesis (SPPS).

Main Methods:

• Route A: Reaction of halo acid esters on 2-chlorotrityl (Cltr) resin with N-fluorenylmethoxycarbonyl (Fmoc) aminothiols, followed by cleavage or direct peptide elongation.
• Route B: Reaction of N-Fmoc aminothiols with bromoacetylated peptides synthesized on Cltr-resin, followed by Fmoc deprotection and elongation.
• Route C: Condensation of haloacylated peptides (on Cltr-resin) with thiol-peptides (on 4-methoxytrityl (Mmt) or trityl (Trt) resin).

Main Results:

• Successfully synthesized thioether-containing peptides via three distinct chemical pathways.
• Demonstrated the utility of N-Fmoc protected (aminothiol)carboxylic acids as key building blocks in SPPS.
• Established methods for peptide chain elongation and condensation either in solution or on solid support.

Conclusions:

• The three developed routes offer versatile strategies for synthesizing thioether-containing peptides.
• These methods provide access to novel peptide structures with potential applications in various scientific fields.
• The study contributes to the advancement of peptide synthesis methodologies.