Solid-phase synthesis of multiple classes of peptidomimetics from versatile resin-bound aldehyde intermediates

Area of Science:

• Organic Chemistry
• Medicinal Chemistry
• Synthetic Chemistry

Background:

• Peptidomimetics are crucial for drug discovery, offering improved stability and bioavailability over natural peptides.
• Developing efficient synthetic routes for diverse peptidomimetic scaffolds is essential for combinatorial chemistry and lead optimization.

Purpose of the Study:

• To develop a versatile solid-phase synthesis for highly substituted lactam-containing peptidomimetic scaffolds.
• To demonstrate the utility of resin-bound aldehyde intermediates for constructing diverse cyclic structures.
• To explore the application of these scaffolds in combinatorial chemistry and modified peptide synthesis.

Main Methods:

• Solid-phase synthesis utilizing a single class of resin-bound aldehyde intermediates.
• Preparation of monocyclic, bicyclic, tricyclic, and tetracyclic lactam scaffolds.
• Cyclitive cleavage for final product release from the resin support.

Main Results:

• Successful synthesis of a wide variety of highly substituted lactam-containing peptidomimetics.
• Demonstration of facile construction of diverse substitution patterns from readily synthesized intermediates.
• High purity of final products achieved through cyclitive cleavage, even with simple filtration workups.

Conclusions:

• The developed solid-phase synthesis provides a versatile platform for generating diverse peptidomimetic scaffolds.
• The methodology is well-suited for combinatorial chemistry applications.
• Mild reaction conditions allow for potential use in constructing modified peptides and peptide segments with conformationally restricted linkers.