ABSTRACT
The development of turn-based inhibitors of protein-protein interactions has attracted considerable attention in medicinal chemistry. Our group has synthesized a series of peptides derived from an amino-functionalized ferrocene to investigate their potential to mimic protein turn structures. Detailed DFT and spectroscopic studies (IR, NMR, CD) have shown that, for peptides, the backbone chirality and bulkiness of the amino acid side chains determine the hydrogen-bond pattern, allowing tuning of the size of the preferred hydrogen-bonded ring in turn-folded structures. However, their biological potential is more dependent on their lipophilicity. In addition, our pioneering work on the chiroptical properties of aminoferrocene-containing peptides enables the correlation of their geometry with the sign of the CD signal in the absorption region of the ferrocene chromophore. These studies have opened up the possibility of using aminoferrocene and its derivatives as chirooptical probes for the determination of various chirality elements, such as the central chirality of amino acids and the helicity of peptide sequences.
Subject(s)
Amino Acids , Ferrous Compounds , Metallocenes , Peptides , Ferrous Compounds/chemistry , Amino Acids/chemistry , Metallocenes/chemistry , Peptides/chemistry , Hydrogen Bonding , StereoisomerismABSTRACT
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, ß-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 ß-turns. Cell viability study, clonogenic assay and cell death analysis showed the highest biological potential of homochiral peptide 4.
Subject(s)
Carboxylic Acids/chemistry , Carboxylic Acids/pharmacology , Cell Proliferation/drug effects , Ferrous Compounds/chemistry , Ferrous Compounds/pharmacology , Peptidomimetics/chemistry , Peptidomimetics/pharmacology , Cell Line, Tumor , Cell Survival/drug effects , Crystallography, X-Ray/methods , Dipeptides/chemistry , Dipeptides/pharmacology , HeLa Cells , Humans , MCF-7 Cells , Peptides/chemistry , Peptides/pharmacology , Protein Structure, Secondary , StereoisomerismABSTRACT
The title compound, [Fe(C6H5O2)(C10H13O2)], contains a heteroannularly substituted ferrocene unit, with the two substituents, viz. 3-(methoxycarbonyl)propyl and carboxyl, both capable of forming O-H...O hydrogen bonds. The keto ester group is stereochemically hindered by the trimethylene spacer and does not participate in intramolecular hydrogen-bond formation. Instead, the carboxy groups form self-complementary intermolecular hydrogen bonds [O...O = 2.650 (2) A], which join the molecules into centrosymmetric dimers with a graph-set descriptor R(2)2(8).
