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

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 -andpool synthesis. We showcase our technology's unique power for efficiently generating diverse macrocycle sizes by synthesizing a series of potent and selective integrin inhibitors.