Spirolactams as conformationally restricted pseudopeptides: synthesis and conformational analysis

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Peptide synthesis often requires constrained analogues to mimic specific secondary structures.
• Tachykinins contain a conserved C-terminal tripeptide motif crucial for their biological activity.
• Developing mimetics of these motifs can lead to novel therapeutic agents.

Purpose of the Study:

• To synthesize novel constrained dipeptide surrogates of Pro-Leu and Gly-Leu.
• To synthesize tripeptide analogues mimicking the C-terminal region of tachykinins.
• To analyze the conformational properties of these novel peptide analogues.

Main Methods:

• Synthesis of 1-(tert-butoxycarbonyl)-7-[1-(tert-butoxycarbonyl)-3-methylbutyl]-6-oxo-1,7-diazaspiro[4.5]decanes.
• Preparation of constrained dipeptide surrogates.
• Synthesis of Ac-[Gly-Leu]-Met-NH(2) derivatives.
• Nuclear Magnetic Resonance (NMR) spectroscopy.
• Molecular modeling calculations.

Main Results:

• Successful synthesis of spirocyclic compounds and peptide derivatives.
• Identification of constrained surrogates for Pro-Leu and Gly-Leu dipeptides.
• Characterization of Ac-[Gly-Leu]-Met-NH(2) analogues (S,S,S)-2a and (S,R,S)-2b.
• Conformational analysis revealed gamma-turn/distorted type II beta-turn mimetic properties.

Conclusions:

• The synthesized spirocyclic compounds serve as effective constrained surrogates for dipeptides.
• The tripeptide analogues mimic key structural features of tachykinins.
• These analogues represent valuable tools for peptide research and drug discovery, particularly for targeting peptide-protein interactions.