Issue 11, 2016

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

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

Supplementary files

Article information

Article type
Edge Article
Submitted
16 Apr. 2016
Accepted
29 Jūn. 2016
First published
30 Jūn. 2016
This article is Open Access

All publication charges for this article have been paid for by the Royal Society of Chemistry
Creative Commons BY license

Chem. Sci., 2016,7, 6662-6668

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

This article is licensed under a Creative Commons Attribution 3.0 Unported Licence. You can use material from this article in other publications without requesting further permissions from the RSC, provided that the correct acknowledgement is given.

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