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.
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.|Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada.
Jennifer L
JL
Hickey
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
Serge
S
Zaretsky
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.|Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada.
Megan A
MA
St Denis
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.|Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada.
Sai
S
Kumar Chakka
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.|Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada.
M Monzur
MM
Morshed
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
Conor C G
CC
Scully
Encycle Therapeutics Inc. , 101 College Street, Suite 314, Toronto, Ontario M5G 1L7, Canada.
Andrew L
AL
Roughton
Davenport Research Laboratories, Department of Chemistry, University of Toronto , 80 St. George Street, Toronto, Ontario M5S 3H6, Canada.
Andrei K
AK
Yudin
D000577:Amides / Q000138:chemical synthesis / Q000737:chemistry*; D047028:Macrocyclic Compounds / Q000138:chemical synthesis / Q000737:chemistry*; D008968:Molecular Conformation
D000577:Amides; D047028:Macrocyclic Compounds