Issue 4, 2014

Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

Abstract

Here we describe a general synthetic platform for side-chain macrocyclization of an unprotected peptide library based on the SNAr reaction between cysteine thiolates and a new generation of highly reactive perfluoroaromatic small molecule linkers. This strategy enabled us to simultaneously “scan” two cysteine residues positioned from i, i + 1 to i, i + 14 sites in a polypeptide, producing 98 macrocyclic products from reactions of 14 peptides with 7 linkers. A complementary reverse strategy was developed; cysteine residues within the polypeptide were first modified with non-bridging perfluoroaryl moieties and then commercially available dithiol linkers were used for macrocyclization. The highly convergent, site-independent, and modular nature of these two strategies coupled with the unique chemoselectivity of a SNAr transformation allows for the rapid diversity-oriented synthesis of hybrid macrocyclic peptide libraries with varied chemical and structural complexities.

Graphical abstract: Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

Supplementary files

Article information

Article type
Paper
Submitted
01 Nov 2013
Accepted
19 Nov 2013
First published
06 Dec 2013

Org. Biomol. Chem., 2014,12, 566-573

Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

Y. Zou, A. M. Spokoyny, C. Zhang, M. D. Simon, H. Yu, Y. Lin and B. L. Pentelute, Org. Biomol. Chem., 2014, 12, 566 DOI: 10.1039/C3OB42168F

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements