Stereoisomerism of Stapled Peptide Inhibitors of the p53-Mdm2 Interaction: An Assessment of Synthetic Strategies and Activity Profiles

Stereoisomerism of Stapled Peptide Inhibitors of the p53-Mdm2 Interaction: An Assessment of Synthetic Strategies and Activity Profiles
Title:
Stereoisomerism of Stapled Peptide Inhibitors of the p53-Mdm2 Interaction: An Assessment of Synthetic Strategies and Activity Profiles
Other Titles:
Chemical Science
Publication Date:
30 May 2019
Citation:
Chem. Sci., 2019,10, 6457-6466
Abstract:
All-hydrocarbon, i, i+7 stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis via olefin metathesis results in the formation of both E- and Z-isomers, an observation that is rarely disclosed but may be of importance in targeting PPI. In this study, we evaluated the effect of staple geometry on the biological activity of five p53-reactivating peptides. We also present strategies for the modulation of the E/Z ratio and attainment of the hydrogenated adduct through repurposing of the metathesis catalyst.
License type:
http://creativecommons.org/licenses/by-nc/4.0/
Funding Info:
This research was funded by the A*STAR JCO Visiting Investigatorship Programme (JCO 1235d00048) and the Industry Alignment Fund (Pre-positioning, HBMS domain H17/01/a0/010).
Description:
ISSN:
2041-6520
2041-6539
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