Conformational Preferences and Antiproliferative Activity of Peptidomimetics Containing Methyl 1′-Aminoferrocene-1-carboxylate and Turn-Forming Homo- and Heterochiral Pro-Ala Motifs

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.

Hydrogen Bonding Drives Helical Chirality via 10-Membered Rings in Dipeptide Conjugates of Ferrocene-1,1′-Diamine

“…Based on our previous results on the antitumor activity of ferrocene peptidomimetics, it was found that lipophilicity contributes significantly to the biological activity, i.e., ferrocene peptidomimetics with larger retention factors ( R f ) in less polar solvents showed better antiproliferative capacity [ 19 , 27 , 28 , 29 ]. However, the results obtained here are only partially consistent with the previous findings and are more dependent on the cell line treated (the HepG2 cell line was resistant to the peptides tested, whereas the HeLa cell line was sensitive only to Leu-peptides 34/37 , and Phe-peptides 32/35 affected only the MCF-7 cell line).…”

“…As found in the in vitro evaluation of the anticancer activity of the ferrocene peptidomimetics tested so far in our group [ 19 , 27 , 28 , 29 ], the lipophilicity of ferrocene conjugates III [ 19 ] was of crucial influence on the cytotoxic activity and compounds with larger retention factors ( R f ) showed better antiproliferative activity. The outstanding potential of the ferrocene scaffold –NH–Fn–NH– to induce a stable β-sheet-like structure in the conjugates III when coupled with Ala raises the question of whether its conjugates with other amino acids would adopt the same folding pattern and exhibit enhanced biological activity.…”

Novel ferrocene imide derivatives: synthesis, conformational analysis and X-ray structure

“…It is based on three-step approach starting from the lowest level of theory (OPLS2005 force field, Monte Carlo conformational search algorithms) and only the representative sets of conformers were submitted further to full DFT optimizations in chloroform and verified as minima on the potential energy surface. We particularly chose chloroform based on our previous studies where computational data were tested against the NMR experiments to detect the most stable conformers [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. To simplify this study, trinuclear complexes were not individually analysed due to the fact that imide linkage between the second and the third ferrocene unit is assumed to be the same as between the first and the second ferrocene unit [ 12 ].…”

“…Conformational analysis was performed in three stages for each of the five compounds ( 4 , 5 , 7 , 9 and 10 ). This approach was already used in many of our investigations regarding mono- and disubstituted ferrocenes [ 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 , 37 ]. Low-level optimizations were performed in MacroModel [ 38 , 39 ] and OPLS2005 force field was used with different search algorithms to obtain the best set of geometries at the molecular mechanics level of theory.…”

Biological Evaluation and Conformational Preferences of Ferrocene Dipeptides with Hydrophobic Amino Acids

“…Although many organic compounds and natural products with incorporated ferrocene units [29] have been investigated as potential drugs [30] due to the desirable properties of ferrocene (non-toxicity, stability, and lipophilicity), the literature on the bioactivity of 1,1 -disubstituted ferrocene peptides is very limited. To date, only a few studies on their biological activity have been performed, most of them carried out by our group to provide a guide for the development of potential drug candidates [6,[31][32][33]. Unfortunately, conjugates with the incorporated −NH−Fn−CO− template [Y-Fca-Pro-OMe (I, Y = Ac, Boc), Y-Pro-Fca-OMe (II, Y = Ac, Boc), and homo-and heterochiral Y-Pro-Ala-Fca-OMe (III, Y = Ac, Boc)] showed no or rather modest antiproliferative activity on MCF-7 and HeLa cell lines.…”