Peptide Macrocyclization Inspired by Non-Ribosomal Imine Natural Products

Lara R. Malins, Justine N. Degruyter, Kevin J. Robbins, Paul M. Scola, Martin D. Eastgate, M. Reza Ghadiri, Phil S. Baran*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

91 Citations (Scopus)

Abstract

A thermodynamic approach to peptide macrocyclization inspired by the cyclization of non-ribosomal peptide aldehydes is presented. The method provides access to structurally diverse macrocycles by exploiting the reactivity of transient macrocyclic peptide imines toward inter- and intramolecular nucleophiles. Reactions are performed in aqueous media, in the absence of side chain protecting groups, and are tolerant of all proteinogenic functional groups. Macrocyclic products bearing non-native and rigidifying structural motifs, isotopic labels, and a variety of bioorthogonal handles are prepared, along with analogues of four distinct natural products. Structural interrogation of the linear and macrocyclic peptides using variable-temperature NMR and circular dichroism suggests that preorganization of linear substrates is not a prerequisite for macrocyclization.

Original languageEnglish
Pages (from-to)5233-5241
Number of pages9
JournalJournal of the American Chemical Society
Volume139
Issue number14
DOIs
Publication statusPublished - 12 Apr 2017
Externally publishedYes

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