Abstract
The concept of peptidomimetics is based on structural modifications of natural peptides that aim not only to mimic their 3D shape and biological function, but also to reduce their limitations. The peptidomimetic approach is used in medicinal chemistry to develop drug-like compounds that are more active and selective than natural peptides and have fewer side effects. One of the synthetic strategies for obtaining peptidomimetics involves mimicking peptide α-helices, β-sheets or turns. Turns are usually located on the protein surface where they interact with various receptors and are therefore involved in numerous biological events. Among the various synthetic tools for turn mimetic design reported so far, our group uses an approach based on the insertion of different ferrocene templates into the peptide backbone that both induce turn formation and reduce conformational flexibility. Here, we conjugated methyl 1′-aminoferrocene-carboxylate with homo- and heterochiral Pro-Ala dipeptides to investigate the turn formation potential and antiproliferative properties of the resulting peptidomimetics 2–5. Detailed spectroscopic (IR, NMR, CD), X-ray and DFT studies showed that the heterochiral conjugates 2 and 3 were more suitable for the formation of β-turns. Cell viability study, clonogenic assay and cell death analysis showed the highest biological potential of homochiral peptide 4.
Highlights
One of the synthetic approaches in the development and optimization of pep tidomimetics is based on mimicking the peptide secondary structures (α-helices, β-sheet or turns) involved in protein-protein interactions (PPIs) [3]
Results and Discussion ceptors expressed on cancer cells, ferrocene-amino acid/peptide hybrids could be used to
We have shown that even monosubstituted aminoferrocene incorporated at the C-terminus of di- and tripeptide sequences can sense the chiral environment (Mθ ~ 1000–2000 deg cm2 dmol−1 ) resulting from the turn structures established in the attached peptide fragment [19,20]
Summary
Despite their enormous biological importance and drug-like properties, the medical use of peptides is still limited by their poor proteolytic stability, poor absorption, and low selectivity. One of the synthetic approaches in the development and optimization of peptidomimetics is based on mimicking the peptide secondary structures (α-helices, β-sheets or turns) 4.0/). One of the synthetic approaches in the development and optimization of pep tidomimetics is based on mimicking the peptide secondary structures (α-helices, β-sheet or turns) involved in protein-protein interactions (PPIs) [3]. Pro tein-protein interfaces have bioactive “hotspots” consisting of four to eight amino acid segments, and half of them are arranged [4].a cell, The PPIs development of mimetics of PPI involved in protein-protein interactions (PPIs)in [3].turns
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