Biocompatible Synthesis of Macrocyclic Thiazol(in)e Peptides

Area of Science:

• Medicinal Chemistry
• Organic Synthesis
• Biochemistry

Background:

• Macrocyclic peptides with thiazole/thiazoline backbones are valuable in drug discovery due to enhanced bioactivity, stability, and permeability.
• These privileged structures are found in numerous natural products and pharmaceuticals.

Purpose of the Study:

• To present a novel, biocompatible synthesis of macrocyclic peptides.
• To establish a metal-free and rapid pathway for generating thiazole-containing macrocycles.

Main Methods:

• Incorporation of N-terminal cysteine during solid-phase peptide synthesis.
• Introduction of C-terminal nitrile via cleavage with aminoacetonitrile using a cleavable linker.
• Biocompatible cyclization in buffer at physiological pH and room temperature.
• Mild, metal-free oxidation of thiazoline to thiazole using alkaline salt and air.

Main Results:

• Direct yield of fully functionalized linear peptide precursors.
• Stable thiazoline heterocycle formation under physiological conditions.
• Conversion to stable thiazole macrocyclic peptides without metal catalysts.
• Hydrolysis of thiazoline provides access to amide backbone macrocyclic peptides.

Conclusions:

• A rapid, biocompatible, and metal-free method for synthesizing macrocyclic thiazole peptides is established.
• The developed protocol leverages readily available reagents and mild conditions.
• This approach facilitates the generation of privileged macrocyclic peptide structures for pharmaceutical applications.