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Issue 6, 2017
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Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

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Abstract

Macrocyclic peptides are important therapeutic candidates due to their improved physicochemical properties in comparison to their linear counterparts. Here we detail a method for a divergent macrocyclisation of unprotected peptides by crosslinking two cysteine residues with bis-palladium organometallic reagents. These synthetic intermediates are prepared in a single step from commercially available aryl bis-halides. Two bioactive linear peptides with cysteine residues at i, i + 4 and i, i + 7 positions, respectively, were cyclised to introduce a diverse array of aryl and bi-aryl linkers. These two series of macrocyclic peptides displayed similar linker-dependent lipophilicity, phospholipid affinity, and unique volume of distributions. Additionally, one of the bioactive peptides showed target binding affinity that was predominantly affected by the length of the linker. Collectively, this divergent strategy allowed rapid and convenient access to various aryl linkers, enabling the systematic evaluation of the effect of appending unit on the medicinal properties of macrocyclic peptides.

Graphical abstract: Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

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Supplementary files

Article information


Submitted
13 Dec 2016
Accepted
13 Mar 2017
First published
24 Mar 2017

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

Chem. Sci., 2017,8, 4257-4263
Article type
Edge Article

Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

A. J. Rojas, C. Zhang, E. V. Vinogradova, N. H. Buchwald, J. Reilly, B. L. Pentelute and S. L. Buchwald, Chem. Sci., 2017, 8, 4257
DOI: 10.1039/C6SC05454D

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