Abstract
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.
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website at DOI: 10.1021/acs.jmedchem.6b00222.
Additional information detailing the PAMPA methodology and results, aqueous solubility, cLogP and PSA calculations, NMR spectra, and X-ray crystallography data (PDF)
Crystallographic information for compound 1 (CIF)
Crystallographic information for compound 9 (CIF)
Three-dimensional structure for TOC graphic (PDB)
Three-dimensional structure for Figure 2 (PDB)
Molecular formula strings (CSV)
