Peptide Macrocycles Developed from Precisely Regulated Multiple Cyclization of Unprotected Peptides

Peptide macrocycles have been attractive scaffolds for the development of ligands and inhibitors to proteins, which have the potential of being developed as potent drugs. Novel strategies for peptide macrocyclization should be of particular interest to peptide drug design and discovery. Herein, an efficient strategy for designing and synthesizing macrocyclic peptides, which relies on the precisely regulated and efficient one-pot cyclization of unprotected peptides with 2,3,5,6-tetrafluoroterephthalonitrile (4F-2CN), is reported. The peptide bicycles can be considered as novel structurally hyperconstrained peptide macrocycles constrained with a rigidifying ring-closing moiety, consisting of an N-terminal 6-membered ring and C-terminal 13-membered ring fused with the benzene ring of 4F-2CN. These novel macrocyclic peptide scaffolds would be intriguing and promising scaffolds for developing macrocyclic peptide inhibitors and targeting ligands for many proteins.