Passive Membrane Permeability of Macrocycles Can Be Controlled by Exocyclic Amide Bonds

We
have developed a strategy for synthesizing passively permeable
peptidomimetic macrocycles. The cyclization chemistry centers on using
aziridine aldehydes in a multicomponent reaction with peptides and
isocyanides. The linker region in the resulting product contains an
exocyclic amide positioned α to the peptide backbone, an arrangement
that is not found among natural amino acids. This amide provides structural
rigidity within the cyclic peptidomimetic and promotes the creation
of a stabilizing intramolecular hydrogen bonding network. This exocyclic
control element also contributes to the increased membrane permeability
exhibited by multicomponent-derived macrocycles with respect to their
homodetic counterparts. The exocyclic control element is employed
along with a strategic placement of N-methyl and d-amino acids to produce passively permeable peptides, which
contain multiple polar residues. This strategy should be applicable
in the pursuit of synthesizing therapeutically relevant macrocycles.