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Stereoisomerism of stapled peptide inhibitors of the p53-Mdm2 interaction: an assessment of synthetic strategies and activity profiles

2019; Royal Society of Chemistry; Volume: 10; Issue: 26 Linguagem: Inglês

10.1039/c9sc01456j

2041-6539

Tsz Ying Yuen, Christopher J. Brown, Yuezhen Xue, Yaw Sing Tan, Fernando Jose Ferrer Gago, Xue Er Lee, Jin Yong Neo, Dawn Thean, Hung Yi Kristal Kaan, Anthony W. Partridge, Chandra Verma, David P. Lane, Charles W. Johannes,

Cancer-related Molecular Pathways

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.