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

• Published in: Organic & biomolecular chemistry Vol. 17; no. 34; pp. 814 - 818
• Main Authors: Sharma, Krishna, Strizhak, Alexander V, Fowler, Elaine, Wang, Xuelu, Xu, Wenshu, Hatt Jensen, Claus, Wu, Yuteng, Sore, Hannah F, Lau, Yu Heng, Hyvönen, Marko, Itzhaki, Laura S, Spring, David R
• Format: Journal Article
• Language: English
• Published: CAMBRIDGE Royal Soc Chemistry 28.08.2019; Royal Society of Chemistry
• Subjects: Alkynes; Alkynes - chemistry; Animals; Aqueous solutions; Azides - chemistry; Biocompatibility; Cell Line; Chemical synthesis; Chemistry; Chemistry, Organic; Click Chemistry; Cycloaddition Reaction; Escherichia coli; Humans; MDM2 protein; Mice; Organic chemistry; p53 Protein; Peptides; Peptides - chemical synthesis; Peptides - pharmacology; Physical Sciences; Protein Binding - drug effects; Proto-Oncogene Proteins c-mdm2 - metabolism; Reagents; Science & Technology; Solubility; System effectiveness; Triazoles - chemical synthesis; Triazoles - pharmacology; Tumor Suppressor Protein p53 - metabolism; Water - chemistry; TARGET; CYCLOADDITION; APOPTOSIS; DESIGN; MDM2; LIGATION; STAPLED PEPTIDES; INHIBITOR; BINDING; MACROCYCLIZATION
• ISSN: 1477-0520; 1477-0539
• DOI: 10.1039/c9ob01745c

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. The Sondheimer dialkyne is extensively used in double strain-promoted azide-alkyne cycloadditions.