Chemically revertible molecular clasps: Hydroxamic acid-mediated peptide macrocyclization and linearization

Summary

Small macrocyclic peptides are valuable modalities due to their potency and biocompatibility. Novel synthetic methods are needed, particularly for small, stable head-to-tail-linked macrocycles that can be linearized in response to stimuli. We detail a method for the cyclization of unprotected peptides bearing a C-terminal hydroxamic acid and an N-terminal electrophile to generate hydroxamate-containing head-to-tail-cyclized peptidomimetics. The key hydroxamate linkage is stable and of low molecular weight and can be cleaved chemoselectively in the presence of all canonical amino acid residues. The C-terminal hydroxamic acid is easily installed using solid-phase peptide synthesis. Its alkylation occurs under aqueous conditions in the presence of unprotected, thiol-free amino acid residues. A range of macrocycle ring sizes (13–40+ atoms) are accessed. The strategy is compatible with non-canonical amino acid residues and split-and-pool synthesis. We showcase our technology's unique power for efficiently generating diverse macrocycle sizes by synthesizing a series of potent and selective integrin inhibitors.