Abstract
The Sondheimer dialkyne reagent has previously been employed in strain-promoted double-click cycloadditions with bis-azide peptides to generate stapled peptide inhibitors of protein-protein interactions. The substituted variants of the Sondheimer dialkyne can be used to generate functionalized stapled peptide inhibitors with improved biological properties; however, this remains a relatively underdeveloped field. Herein, we report the synthesis of new substituted variants of Sondheimer dialkyne and their application in the stapling of p53-based diazido peptides to generate potent stapled peptide-based inhibitors of the oncogenic p53-MDM2 interaction. The functionalized stapled peptide formed from a meta-fluoro-substituted Sondheimer dialkyne was found to be the most potent inhibitor. Furthermore, through experimental studies and density functional theory calculations, we investigated the impact of the substituent on the strain-promoted double-click reactivity of Sondheimer dialkyne.
| Original language | English |
|---|---|
| Pages (from-to) | 1157-1169 |
| Number of pages | 13 |
| Journal | ACS Omega |
| Volume | 5 |
| Issue number | 2 |
| DOIs | |
| Publication status | Published - 21 Jan 2020 |
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. M.N.G. thanks the University of Bath for financial support. B.C. thanks Herchel Smith Trust for funding. We thank Dr. Andrew Bond for X-ray crystallography, Balasubrmanian group (Department of Chemistry, University of Cambridge) for use of their UV spectrometer, and the PNAC service (Department of Biochemistry, University of Cambridge). We would like to thank X-ray crystallographic facility at the Department of Biochemistry for access to crystallisation instrumentation. We are grateful for the Diamond Light Source for access to beamline I04 (proposal mx14043) and for the data that contributed to these results. Part of this work was performed using the Darwin Supercomputer of the University of Cambridge High Performance Computing Service ( http://www.hpc.cam.ac.uk/ ), provided by Dell Inc. using Strategic Research Infrastructure Funding from the Higher Education Funding Council for England and funding from the Science and Technology Facilities Council.
Publisher Copyright:
© 2020 American Chemical Society.