Issue 34, 2019

Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry

Abstract

The Sondheimer dialkyne is extensively used in double strain-promoted azide–alkyne cycloadditions. This reagent suffers with poor water-solubility and rapidly decomposes in aqueous solutions. This intrinsically limits its application in biological systems, and no effective solutions are currently available. Herein, we report the development of novel highly water-soluble, stable, and azide-reactive strained dialkyne reagents. To demonstrate their extensive utility, we applied our novel dialkynes to a double strain-promoted macrocyclisation strategy to generate functionalised p53-based stapled peptides for inhibiting the oncogenic p53-MDM2 interaction. These functionalised stapled peptides bind MDM2 with low nanomolar affinity and show p53 activation in a cellular environment. Overall, our highly soluble, stable and azide-reactive dialkynes offer significant advantages over the currently used Sondheimer dialkyne, and could be utilised for numerous biological applications.

Graphical abstract: Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry

Supplementary files

Article information

Article type
Paper
Submitted
06 Feb 2019
Accepted
09 Aug 2019
First published
09 Aug 2019

Org. Biomol. Chem., 2019,17, 8014-8018

Water-soluble, stable and azide-reactive strained dialkynes for biocompatible double strain-promoted click chemistry

K. Sharma, A. V. Strizhak, E. Fowler, X. Wang, W. Xu, C. Hatt Jensen, Y. Wu, H. F. Sore, Y. H. Lau, M. Hyvönen, L. S. Itzhaki and D. R. Spring, Org. Biomol. Chem., 2019, 17, 8014 DOI: 10.1039/C9OB01745C

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