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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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Supplementary files

Article information


Submitted
16 Apr 2016
Accepted
29 Jun 2016
First published
30 Jun 2016

This article is Open Access
All publication charges for this article have been paid for by the Royal Society of Chemistry

Chem. Sci., 2016,7, 6662-6668
Article type
Edge Article

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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