Substitution Effects of Alkene Dipeptide Isosteres on Adjacent Peptide Bond Rotation

Abstract

Alkene dipeptide isosteres (ADIs) are promising surrogates of peptide bonds that enhance the bioactive peptide resistance to enzymatic hydrolysis in medicinal chemistry. In this study, we investigated the substitution effects of an ADI on the energy barrier of cis–trans isomerization in the acetyl proline methyl ester (Ac-Pro-OMe) model. The (E)-alkene-type proline analog, which favors a cis-amide conformation, exhibits a lower rotational barrier than native Ac-Pro-OMe. A van’t Hoff analysis suggests that the energy barrier is primarily reduced by enthalpic repulsion. It was concluded that although carbon–carbon double bonds and pyrrolidine rings individually increase the rigidity of the incorporation site, their combination can provide structural flexibility and disrupt bioactive conformations. This work provides new insights into ADI-based drug design.