Diversity-oriented synthesis of macrocyclic peptidomimetics.

Area of Science:

• Medicinal Chemistry
• Organic Synthesis

Background:

• Novel small molecules are crucial for discovering biologically active agents.
• Macrocyclic peptidomimetics are underrepresented in screening collections due to synthetic challenges.

Purpose of the Study:

• To develop a diversity-oriented synthesis strategy for novel macrocyclic peptidomimetics.
• To generate diverse small molecules for biological screening.

Main Methods:

• Implemented a diversity-oriented synthesis strategy.
• Developed novel macrocyclic ring closure methods for chiral α-azido acids.
• Utilized solid-supported N-methylmorpholine for diketopiperazine synthesis.

Main Results:

• Successfully synthesized a library of 14 diverse macrocyclic peptidomimetic compounds.
• Demonstrated that the synthesized compounds occupy underrepresented areas of chemical space.
• Validated novel synthetic methodologies for macrocyclization and diketopiperazine formation.

Conclusions:

• The developed strategy effectively generates diverse small molecules with potential biological activity.
• The novel synthetic methodologies are robust, flexible, and applicable in broader synthetic contexts.
• This work addresses the synthetic intractability of macrocyclic peptidomimetics, enhancing their accessibility for drug discovery.