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.
| Original language | English |
|---|---|
| Pages (from-to) | 8014-8018 |
| Number of pages | 5 |
| Journal | Organic and Biomolecular Chemistry |
| Volume | 17 |
| Issue number | 34 |
| DOIs | |
| Publication status | Published - 2019 |
Bibliographical note
Funding Information:D. R. S. acknowledges support from the Engineering and Physical Sciences Research Council (EP/P020291/1) and Royal Society (Wolfson Research Merit Award). K. S. would like to thank Trinity College, Cambridge Trust, Cambridge Nehru Trust and the Cambridge Philosophical Society for providing fellowships. We would like to thank X-ray crystallographic facility at the Department of Biochemistry for access to crystallisation instrumentation and the PNAC service (Department of Biochemistry, University of Cambridge). We are grateful for the Diamond Light Source for access to beamline I04 (proposal mx14043) and for the data that contributed to these results.
Publisher Copyright:
This journal is © The Royal Society of Chemistry.