Pentelute Lab MIT | Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation
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.
Pentelute Lab, MIT, Cambridge, Chemistry, Molecular biology, technology development, peptide, protein-based therapeutics, chemical Biology, Bradley Pentelute
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Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

Divergent unprotected peptide macrocyclisation by palladium-mediated cysteine arylation

Chem. Sci. (2017)
8, 4257-4263
Published: The article was received on 13 Dec 2016, accepted on 13 Mar 2017 and first published on 24 Mar 2017

Authors: Anthony J. Rojas, Chi Zhang, Ekaterina V. Vinogradova, Nathan H. Buchwald, John Reilly, Bradley L. Pentelute and Stephen L. Buchwald

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.

Category
2017, Publications