Oxadiazole grafts in peptide macrocycles

• Published in: Nature chemistry Vol. 8; no. 12; pp. 1105 - 1111
• Main Authors: Frost, John R., Scully, Conor C. G., Yudin, Andrei K.
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.12.2016; Springer Nature; Nature Publishing Group
• Subjects: 140/131; 140/58; 631/154/309/2144; 639/638/403/933; 639/638/92/611; Aldehydes; Analytical Chemistry; Bioavailability; Biochemistry; Chemistry; Chemistry, Multidisciplinary; Chemistry/Food Science; Conformation; Control methods; Drug development; Grafts; Hydrogen; Inorganic Chemistry; Membrane permeability; Natural products; Organic Chemistry; Oxadiazoles; Peptides; Peptidomimetics; Permeability; Physical Chemistry; Physical Sciences; Polarity; Science & Technology; PASSIVE MEMBRANE-PERMEABILITY; (N-ISOCYANIMINO)TRIPHENYLPHOSPHORANE; ONE-POT; LINEAR PEPTIDES; ABSORPTION; SCAFFOLDS; 1,3,4-OXADIAZOLE; BOND ORBITAL ANALYSIS; CYCLIC-PEPTIDES; STRUCTURAL MIMICRY
• ISSN: 1755-4330; 1755-4349
• DOI: 10.1038/nchem.2636

Synthetic methods that provide control over macrocycle conformation and, at the same time, mitigate the polarity of peptide bonds represent valuable tools for the discovery of new bioactive molecules. Here, we report a macrocyclization reaction between a linear peptide, an aldehyde and ( N -isocyanimino)triphenylphosphorane. This process generates head-to-tail cyclic peptidomimetics in a single step. This method is tolerant to variation in the peptide and aldehyde components and has been applied for the synthesis of 15-, 18-, 21- and 24-membered rings. The resulting peptide macrocycles feature a 1,3,4-oxadiazole and a tertiary amine in their scaffolds. This non-canonical backbone region acts as an endocyclic control element that promotes and stabilizes a unique intramolecular hydrogen-bond network and can lead to macrocycles with conformationally rigid turn structures. Oxadiazole-containing macrocycles can also display a high passive membrane permeability, an important property for the development of bioavailable peptide-based therapeutics. Controlling macrocycle conformation represents a powerful tool for the construction of new bioactive molecules. Now, peptide-based macrocycles bearing a 1,3,4-oxadiazole moiety grafted into their backbone have been synthesized via a new cyclization approach. The resulting cyclic products exhibit conformationally rigid turn structures (stabilized through intramolecular hydrogen bonding) that can display passive membrane permeability.