Roesner S,
Saunders GJ,
Wilkening I,
Jayawant E,
Geden JV,
Kerby P,
Dixon AM,
Notman R,
Shipman M.
* University of Warwick, Coventry, UK
Macrocyclisation of Small Peptides Enabled by Oxetane Incorporation.
Chem. Sci. 2019;
10: 2465-2472
Key words
cyclic peptides - macrocyclization - oxetane - disulfide bond - amino acids
Significance
Cyclic peptides have recently emerged as a new source of drug molecules, but very few in clinical use are derived from natural sources. The main problem is associated with their synthesis, which often suffers from C-terminal epimerization, cyclooligomerization, and byproduct formation during macrocyclization. Shipman and co-workers have developed a simple, mild, and efficient macrocyclization strategy, which involves the incorporation of an oxetane ring, for synthesizing cyclic peptides in good yields by using an appropriate coupling reagent.
Comment
Cyclic peptide drugs are more useful than the linear peptides, but their synthesis is quite challenging. The present approach shows that macrocyclization of head-to-tail peptide can be improved by substituting one of the backbone amide C=O bonds with a simple oxetane ring. In addition, a variety of cyclic peptides with challenging ring sizes (tetra-, penta-, or hexapeptides) were synthesized. Further study showed that the bioactivity does not change upon replacing the amide C=O bond with an oxetane ring.
