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Issue 11, 2016
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The reactivity and conformational control of cyclic tetrapeptides derived from aziridine-containing amino acids

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Abstract

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 β-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 α3β macrocycles, regardless of peptide sequence, nucleophile, aziridine β-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 α3β 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.

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

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Publication details

The article was received on 16 Apr 2016, accepted on 29 Jun 2016 and first published on 30 Jun 2016


Article type: Edge Article
DOI: 10.1039/C6SC01687A
Chem. Sci., 2016,7, 6662-6668
  • Open access: Creative Commons BY license
    All publication charges for this article have been paid for by the Royal Society of Chemistry

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

    B. K. W. Chung, C. J. White, C. C. G. Scully and A. K. Yudin, Chem. Sci., 2016, 7, 6662
    DOI: 10.1039/C6SC01687A

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