Diversity-Oriented Synthesis of ERα Modulators via Mitsunobu Macrocyclization

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Molecular Biology

Background:

• Cyclic peptides offer unique structural properties for drug development.
• Estrogen receptor modulators are crucial for treating ER-positive breast cancers.
• Developing stable and effective peptidomimetics remains a challenge.

Purpose of the Study:

• To expand the diversity of cyclic peptides through novel macrocyclization strategies.
• To synthesize novel peptidomimetic estrogen receptor modulator (PERM) analogs.
• To evaluate the pharmacological properties of newly synthesized PERMs.

Main Methods:

• Elaboration of Mitsunobu macrocyclization with diverse hydroxy acid building blocks.
• Solid-phase synthesis of PERM analogs with varied Nε-amine substituents.
• Assessment of serum peptidase stability, cell penetration, and estrogen receptor alpha binding affinity.

Main Results:

• Successfully synthesized a diverse library of cyclic peptides and PERM analogs.
• PERM analogs demonstrated enhanced stability against serum peptidases.
• Improved cell permeability and increased binding affinity for estrogen receptor alpha were observed.

Conclusions:

• The developed diversity-oriented method offers a new tool for azacyclopeptide construction.
• Optimized PERMs show potential for treating estrogen receptor-positive breast cancers.
• Further structural insights gained can guide the development of more effective ERα modulators.