Incorporating a Monofluoroalkene into the Backbones of Short Peptides: Evaluating the Impact on Local Hydrophobicity

Abstract

The local hydrophobicity of an amino acid residue in a peptide sequence can be determined by measuring the hydrophobicity index (φ0) by reversed‐phase (RP) HPLC. Herein, the impact on the local hydrophobicity of the replacement of an amide by a monofluoroalkene unit in short peptides is discussed. Monofluoroalkene‐containing dipeptides and tripeptides were synthesized, as well as their natural parent compounds, and the hydrophobicity indexes of these short peptides and peptidomimetics were determined. Comparison between the natural parent peptides and their alkene‐containing analogues was made, and the dependence of the peptidomimetic analogues’ behaviour on the pH and the solvent was studied. It was found that the presence of a monofluoroalkene unit enhanced a peptide's hydrophobicity.

Stereoselective Synthesis of Terminal Monofluoroalkenes from Trifluoromethylated Alkenes

“…Among these fluorinated groups, monofluoroalkenes are of high interest . The α-substituted monofluoroalkene motif is well recognized as a bioisostere of the amide bond, whereas the terminal monofluoroalkene motif is considered as a mimic of an enol. , …”

Monofluoroalkene‐Isostere as a 19F NMR Label for the Peptide Backbone: Synthesis and Evaluation in Membrane‐Bound PGLa and (KIGAKI)3

“…Very likely,t he rigidity of the new moiety, [7] the change in local hydrophobicity, [31] andi ts deficiency as ah ydrogen bond donor [7] may have caused as ignificant loss of secondary structure, when incorporatedi nto the a-helical PGLa peptide. Very likely,t he rigidity of the new moiety, [7] the change in local hydrophobicity, [31] andi ts deficiency as ah ydrogen bond donor [7] may have caused as ignificant loss of secondary structure, when incorporatedi nto the a-helical PGLa peptide.…”

“…Despite the generally assumed picture, we can conclude that the concept of a genuine isostere does not completely hold for this monofluoroalkene in the context of the two representative secondary structure elements investigated here. Very likely, the rigidity of the new moiety, the change in local hydrophobicity, and its deficiency as a hydrogen bond donor may have caused a significant loss of secondary structure, when incorporated into the α‐helical PGLa peptide. This effect was especially pronounced in the middle of the sequence, which led to peptide aggregation and substantial loss of activity.…”

Regiodivergent electroreductive defluorinative carboxylation ofgem-difluorocyclopropanes

“…Monofluoroalkenes are considered to be highly valuable skeletons, benefiting from the easily convertible alkenyl groups and fluorine atoms to dramatically improve the metabolic stability, lipophilicity, and bioavailability of the parent molecules. 1,2 As such, many efforts from the synthetic community have been directed towards these diverse monofluoroalkene frameworks. 3 Here, gem -difluorocyclopropanes have recently emerged as privileged precursors in the preparation of monofluorinated alkene structures because of the identification of their ideal fluoroallyl surrogates.…”