Yuen, T. Y.; Brown, C. J.; Tan, Y. S.; Johannes, C. W., Synthesis of chiral alkenyl cyclopropane amino acids for incorporation into stapled peptides. The Journal of Organic Chemistry 2020, 85 (3), 1556-1566.
Abstract:
α,α′-Disubstituted amino acids serve as important non-proteinogenic amino acids in the construction of stabilized helical peptides. To expand the repertoire of α,α′-disubstituted amino acids, chiral alkenyl-containing cyclopropane amino acids were synthesized via a two-step olefination and cyclopropanation procedure. Herein, we report the first example of the use of alkenyl cyclopropane building blocks to constrain MDM2-targeting helical peptides. The increased potency and efficacy associated with C-terminal cyclopropane substitution is postulated to be driven by a combined effect of net hydrophobicity and enhanced protein association rates.
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Funding Info:
This work was supported by the Industry Alignment Fund - Pre-Positioning Programme (IAF-PP) of Agency for Science, Technology and Research (A*STAR) (H1701a0010) and the JCO Visiting Investigatorship Programme of Agency for Science, Technology and Research (A*STAR) (JCO 1235d00048).