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

DOI: 10.1039/C9OB01745C

Authors: Krishna Sharma (University of Cambridge) , Alexander V. Strizhak (University of Cambridge) , Elaine Fowler (University of Cambridge) , Xuelu Wang (University of Cambridge) , Wenshu Xu (University of Cambridge) , Claus Hatt Jensen (University of Cambridge) , Yuteng Wu (University of Cambridge) , Hannah F. Sore (University of Cambridge) , Yu Heng Lau (The University of Sydney) , Marko Hyvonen (University of Cambridge) , Laura S. Itzhaki (University of Cambridge) , David R. Spring (University of Cambridge)
Co-authored by industrial partner: No

Type: Journal Paper
Journal: Organic & Biomolecular Chemistry , VOL 126

State: Published (Approved)
Published: August 2019
Diamond Proposal Number(s): 14043

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.

Subject Areas: Chemistry, Biology and Bio-materials


Instruments: I04-Macromolecular Crystallography

Added On: 29/08/2019 15:49

Discipline Tags:

Biochemistry Chemistry Structural biology Organic Chemistry Life Sciences & Biotech

Technical Tags:

Diffraction Macromolecular Crystallography (MX)