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Issue 4, 2014
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Convergent diversity-oriented side-chain macrocyclization scan for unprotected polypeptides

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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

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Publication details

The article was received on 01 Nov 2013, accepted on 19 Nov 2013 and first published on 06 Dec 2013


Article type: Paper
DOI: 10.1039/C3OB42168F
Citation: Org. Biomol. Chem., 2014,12, 566-573
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    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

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