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


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.

SUBMITTER: Yuen TY 

PROVIDER: S-EPMC6610352 | biostudies-literature | 2019 Jul

REPOSITORIES: biostudies-literature

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

Yuen Tsz Ying TY   Brown Christopher J CJ   Xue Yuezhen Y   Tan Yaw Sing YS   Ferrer Gago Fernando J FJ   Lee Xue Er XE   Neo Jin Yong JY   Thean Dawn D   Kaan Hung Yi Kristal HYK   Partridge Anthony W AW   Verma Chandra S CS   Lane David P DP   Johannes Charles W CW  

Chemical science 20190530 26


All-hydrocarbon, <i>i</i>, <i>i+7</i> stapled peptide inhibitors of the p53-Mdm2 interaction have emerged as promising new leads for cancer therapy. Typical chemical synthesis <i>via</i> olefin metathesis results in the formation of both <i>E</i>- and <i>Z</i>-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  ...[more]

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