Copper‐Free Huisgen Cycloaddition for the 14‐3‐3‐Templated Synthesis of Fusicoccin‐Peptide Conjugates

Mid‐sized molecules have emerged as an attractive chemical space and potentially provide a robust basis for the development of synthetic agents to control intracellular protein interactions. However, the limited cell permeability and chemical tractability of such agents remain to be addressed. We en...

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Bibliographic Details
Published in:Chemistry, an Asian journal an Asian journal, 2020-03, Vol.15 (6), p.742-747
Main Authors: Masuda, Ryoma, Kawasaki, Yuuya, Igawa, Kazunobu, Manabe, Yoshiyuki, Fujii, Hiroshi, Kato, Nobuo, Tomooka, Katsuhiko, Ohkanda, Junko
Format: Article
Language:English
Subjects:
14-3-3
14-3-3 Proteins - chemistry
Azides - chemistry
Catalysis
Chemical synthesis
Chemistry
Copper
Copper - chemistry
Cycloaddition
Cycloaddition Reaction - methods
fusicoccin
Glycosides - chemistry
heteroatom-embedded cycloalkyne
Huisgen cycloaddition
Peptides
Peptides - chemistry
protein-templated reaction
Proteins
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Summary:Mid‐sized molecules have emerged as an attractive chemical space and potentially provide a robust basis for the development of synthetic agents to control intracellular protein interactions. However, the limited cell permeability and chemical tractability of such agents remain to be addressed. We envisioned that target‐templated synthesis of such mid‐sized molecules might provide a solution. Here, we exploited a copper‐free Huisgen cycloaddition for template synthesis using a peptide fragment containing a 4,8‐diazacyclononyne (DACN) moiety and an azide‐containing fusicoccin derivative in the presence or absence of recombinant 14‐3‐3ζ protein in vitro. Time‐course changes in the yield of products demonstrated that the reaction was accelerated in the presence of 14‐3‐3 and one of the regioisomers was generated predominantly, supporting the template effect. Templated tactics: A copper‐free Huisgen cycloaddition of an azide‐containing fusicoccin derivative, and a peptide fragment containing a nitrogen‐embedded cyclic alkyne moiety (DACN) in the presence of 14‐3‐3 protein were evaluated. The results demonstrated that the reaction was accelerated in the presence of 14‐3‐3 and generated one of the regioisomers predominantly, supporting the template effect of 14‐3‐3.
ISSN:1861-4728
1861-471X
DOI:10.1002/asia.202000042