The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids

• Published in: Chemical science (Cambridge) Vol. 7; no. 11; pp. 6662 - 6668
• Main Authors: Chung, Benjamin K. W., White, Christopher J., Scully, Conor C. G., Yudin, Andrei K.
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 01.01.2016
• Subjects: Amides; Amino acids; Chemistry; Chemistry, Multidisciplinary; Determinants; Nucleophiles; Peptides; Physical Sciences; Platforms; Proteins; Science & Technology; Stereochemistry; AZUMAMIDE-E; SH2 DOMAIN; PEPTIDE-BONDS; STRUCTURAL ELUCIDATION; CHLAMYDOCIN; MACROCYCLES; DRUG DISCOVERY; CRYSTAL-STRUCTURES; CHEMICAL-EXCHANGE; SCAFFOLDS
• ISSN: 2041-6520; 2041-6539
• DOI: 10.1039/c6sc01687a

Among the smallest of the macrocyclic peptides, 12- and 13-membered cyclic tetrapeptides are particularly noteworthy because they exhibit a broad spectrum of biological activities due to their innate capacity to mimic beta-turns in proteins. In this report, we demonstrate that aziridine-containing cyclic tetrapeptides offer a platform to interrogate the conformational properties of tetrapeptides. We show that aziridine ring-opening of 12-membered cyclic tetrapeptides yields exclusively 13-membered alpha(3)beta macrocycles, regardless of peptide sequence, nucleophile, aziridine beta-carbon substitution, or stereochemistry. NMR and computational studies on two related aziridine-containing cyclic tetrapeptides revealed that the amide conformations of their N-acyl aziridines are similar, and are likely the determinant of the observed ring-opening regioselectivity. Interestingly, some of the resulting 13-membered alpha(3)beta macrocycles were found to be conformationally heterogeneous. This study on the reactivity and conformational control of aziridine-containing cyclic tetrapeptides provides useful insight on the design and development of macrocyclic therapeutics.