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Rigid Peptide Macrocycles from On-Resin Glaser Stapling.

ABSTRACT: Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled ?-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7?Å) between ?-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing ?-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol ligand, and diisopropylethylamine at room temperature. The efficiency of this ligation was illustrated by the synthesis of (i,i+4)-, (i,i+5)-, (i,i+6)-, and (i,i+7)-stapled BCL-9 ?-helical peptides using the unnatural amino acid propargyl serine. Overall, this procedurally simple method relies on inexpensive and widely available reagents to generate low molecular weight 23-, 26-, 29-, and 32-membered peptide macrocycles.

SUBMITTER: Cistrone PA

PROVIDER: S-EPMC6097620 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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Rigid Peptide Macrocycles from On-Resin Glaser Stapling.

Cistrone Philip A PA Silvestri Anthony P AP Hintzen Jordi C J JCJ Dawson Philip E PE

Chembiochem : a European journal of chemical biology 20180426 10

Peptide macrocycles are widely utilized in the development of high affinity ligands, including stapled α-helices. The linear rigidity of a 1,3-diynyl linkage provides an optimal distance (7 Å) between β-carbons of the i,i+4 amino acid side chains, thus suggesting its utility in stabilizing α-helical structures. Here, we report the development of an on-resin strategy for an intramolecular Glaser reaction between two alkyne-terminated side chains by using copper chloride, an essential bpy-diol lig ...[more]

PMID: 29516601

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