Dynamic chirality influences numerous processes in nature
from
protein folding to catalysis. Azapeptides are peptidomimetics possessing
semicarbazide residues that can interconvert between sp2 and sp3 hybridization, resulting in stereodynamic interconversions
of pseudo-R and -S-configurations
by means of a planar intermediate. Cyclic azapeptides have shown unprecedented
binding affinity to the cluster of differentiation 36 receptor (CD36)
and ability to mitigate macrophage-driven inflammation by modulation
of the toll-like receptor 2/6 pathway. A novel approach to synthesize
cyclic peptides via A3-macrocyclization has been used to
make R- and S-configuration controls
to study the relevance of semicarbazide hybridization for modulator
activity. Nuclear magnetic resonance spectroscopy analysis of potent
cyclic azapeptide CD36 modulators (e.g., 1 and 2) and related cyclic peptides demonstrated that binding affinity
correlated with conformational rigidity, and a hybridization preference
for sp2 > S- > R-sp3 semicarbazide nitrogen configuration was evaluated.
Evidence
of the active conformation and the relevance for dynamic chirality
serve as insights for creating cyclic (aza)peptide CD36 modulators
to curb inflammation.
Metal-free triazole turns: 1,5-Disubstituted peptidyl triazoles are obtained regioselectively from the 1,3-dipolar cycloaddition of peptidyl phosphoranes and azides. Peptide turns are thus formed that contain a conformationally locked cis peptide bond. Being regioselective and free of heavy metals, this reaction may find broad application in chemical biology and medicinal chemistry.
Aza‐propargylglycine (azaPra) peptides are branching points for the synthesis of azapeptide libraries. Efficient alkylation of N‐(Fmoc)hydrazine in solution was found to provide N′‐propargyl fluorenylmethyl carbazate 13, which on activation gave N‐(Fmoc)‐azaPra acid chloride for installation into peptides. Reducing the number of steps on resin for azaPra peptide synthesis, which previously necessitated alkylation of a semicarbazone protected aza‐glycine residue, the new method offers potential for higher yield, as demonstrated by the synthesis of azacyclopeptide 1a, as well as by an alanine scan of this potent cluster of differentiation‐36 receptor (CD36) modulator.
Several C-terminal peptidyl-substituted bis-and tris(electrophiles) were prepared by starting from polymeric phosphoranylidenacetates as acyl anion equivalents. After C-acylations with amino acids and peptide elongation, the obtained peptidyl-phosphoranylideneacetate resins were either cleaved oxidatively, delivering peptidyl-diketo esters, or saponified, leading to immediate decarboxylation. The generated peptidyl-phosphorane could be treated with aldehydes
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