Testing the Potential of the Ferrocene Chromophore as a Circular Dichroism Probe for the Assignment of the Screw-Sense Preference of Tripeptides

Abstract

A combined strategy utilizing experimental (infrared, nuclear magnetic resonance, circular dichroism, X-ray) and computational (time-dependent density functional theory) techniques is illustrated on tripeptides to investigate their chiroptical properties. Eight stereoisomers of monosubstituted ferrocene, Boc-Pro-Pro-Ala-NHFc, have been prepared and conformationally characterized in depth to reach some guidelines for a future design of ferrocene-based chromophores. The origin of the sign change in circular dichroism spectra near the absorption maximum of a ferrocene chromophore (about 470 nm) is strongly correlated with the sign of the dihedral angle describing deviation of the directly attached amide plane from planarity of the cyclopentadienyl ring. These findings may provide some guidelines for the design of new chiroptical ferrocene-based probes for the assignment of the screw-sense preference of short peptides.

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

“…(a) (b) As shown in our previous studies [14,[18][19][20], the increase and strengthening of hydrogen bonding in peptides 2 and 3 leads to a higher degree of chiral organization compared to their counterpart 4 and analogues III [16] and IV [17]. It was expected that heterochiral peptides 2 and 3, which showed less DMSO-induced shifts of NHFn compared to homochiral peptides 4 and 5, would adopt a more stable turn conformations realized by intrastrand hydrogen bonds.…”

“…Boc-depro tection of Boc-L-Ala-NH-Fn-COOMe 1 [16] in the presence of gaseous HCl gave a hydro chloride salt, which was processed with an excess of NEt3 to give the free amine required for the coupling step. Then, C-activated Boc-L-Pro-OH and Boc-D-Pro-OH were added to Our previous studies have shown that even the monosubstituted conjugates between the ferrocene and chiral amino acids or short peptides may induce a different sign in the circular dichroism spectra (CD) near the absorption maximum of a ferrocene chromophore (around 470 nm) [18][19][20]. We have pointed out a strong correlation between the sign of the Cotton effect and the sign of the dihedral angle between two planes, one containing the cyclopentadienyl ring and the other containing amide bond [18][19][20].…”

“…Then, C-activated Boc-L-Pro-OH and Boc-D-Pro-OH were added to Our previous studies have shown that even the monosubstituted conjugates between the ferrocene and chiral amino acids or short peptides may induce a different sign in the circular dichroism spectra (CD) near the absorption maximum of a ferrocene chromophore (around 470 nm) [18][19][20]. We have pointed out a strong correlation between the sign of the Cotton effect and the sign of the dihedral angle between two planes, one containing the cyclopentadienyl ring and the other containing amide bond [18][19][20]. Predominance of a specific conformer arises from the amino acid sequence, which triggers a different helicity of the folded peptide through intramolecular interactions, primarily hydrogen bonds.…”

“…However, the noticeable loss of CD activity for asymmetrically disubstituted ferrocene peptides III [16] and IV [17] (M θ ~500-800 deg cm 2 dmol −1 ) is attributed to the reduction and weakening of hydrogen bonds. We have shown that even monosubstituted aminoferrocene incorporated at the C-terminus of di-and tripeptide sequences can sense the chiral environment (M θ ~1000-2000 deg cm 2 dmol −1 ) resulting from the turn structures established in the attached peptide fragment [19,20].…”

“…Our previous studies have shown that even the monosubstituted conjugates between the ferrocene and chiral amino acids or short peptides may induce a different sign in th circular dichroism spectra (CD) near the absorption maximum of a ferrocene chromo phore (around 470 nm) [18][19][20]. We have pointed out a strong correlation between the sign of the Cotton effect and the sign of the dihedral angle between two planes, one containing the cyclopentadienyl ring and the other containing amide bond [18][19][20]. Predominance o a specific conformer arises from the amino acid sequence, which triggers a different helic ity of the folded peptide through intramolecular interactions, primarily hydrogen bonds The second substituent connected to the opposite cyclopentadienyl ring adds additiona hydrogen bond donor and acceptor sites, resulting with more rigid structure through th subsequent formation of intra-or interstrand hydrogen bonds (HBs) inducing the helica chirality of the ferrocene moiety by restricting the torsional twist about the Cp(centroid) Fe-Cp(centroid) axis.…”