Synthesis of conformationally constrained peptidomimetics using multicomponent reactions

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Structural Biology

Background:

• Constrained peptidomimetics are crucial for drug discovery.
• Developing efficient synthetic routes for these molecules remains a challenge.

Purpose of the Study:

• To report a novel modular synthetic approach for constrained peptidomimetics.
• To explore the diversification potential of the synthetic strategy.
• To investigate the turn-inducing properties of the dihydropyridone scaffold.

Main Methods:

• A three-step synthetic sequence involving two multicomponent reactions.
• Molecular modeling to predict secondary structure.
• X-ray crystallography and Nuclear Magnetic Resonance (NMR) spectroscopy to determine the solid-state and solution-state structures.

Main Results:

• The synthesis allowed for significant diversification of peptide moieties and the scaffold.
• Molecular modeling suggested a type IV beta-turn-like conformation.
• X-ray crystallography and NMR studies revealed an open turn structure, differing from the modeling prediction.

Conclusions:

• The reported modular approach provides efficient access to diverse constrained peptidomimetics.
• The dihydropyridone scaffold adopts an open turn conformation in the solid and solution states.
• Discrepancies between modeling and experimental data highlight the complexity of predicting peptidomimetic structures.