Ferrocene Bioconjugates

In this review we present our recent contribution to the field of bioorganometallic chemistry of ferrocene. Ferrocene conjugates with biomolecules have been synthesized and characterized using IR and NMR (1H, 13C, COSY, NOESY, HMBC) spectroscopy, ESI-MS and HRMS. The bioconjugates of ferrocene with resveratrol (2) and mannose (10, 11, 14 and 15) were biologically evaluated for their potential inhibitory effect on HepG2 cancer cells (2) and E. coli adherence to the bladder epithelium (10, 11, 14 and 15). The oxalamide-bridged ferrocene 17 was sub¬jected to conformational analysis in solution and in the solid state, and tested for its gelation and cytotoxic activity. The mono- (30–32, 36–38, 42–45) and disubstituted ferrocene conjugates with natural amino acids (21–28, 33–35, 39–41, 48, 49, 62–65, 69–72) were subjected to the detailed conformational and DFT analyses in order to determine the turn-inducing potential of ferrocene scaffolds in the corresponding peptidomimetics. This work is licensed under a Creative Commons Attribution 4.0 International License

Synthesis of the First Heteroannularly Substituted Ferrocene Amino Acid and Isomeric Carbamic Acid Derivatives Containing Chiral Centres

Syntheses of N- and C-protected derivatives of 1\u27-(1-aminoethyl)ferrocene-1-carboxylic acid (Fcca) and isomeric carbamic acid are reported. The first attempt to prepare N-Ac-Fcca (8) by cleavage of 1-[1-(acetamido)ethyl]-1\u27-(o-chlorobenzoyl)ferrocene (7) with t-BuOK/H2O/GLYME failed. Friedel-Crafts reactions of N-substituted (1-ferrocenylethyl)amines [Boc-Fea (5) and Ac-Fea (6)] with ClCOSMe/AlCl3 gave the corresponding heteroannularly substituted thioesters 9/10, which were hydrolyzed into Boc-Fcca/Ac-Fcca and esterified into Boc-Fcca-OMe (11)/ Ac-Fcca-OMe (12). In a multi-step sequence, bromoferrocene was transformed into 1’- brominated Fea (15), Boc-Fea (16) and Ac-Fea (17). Lithiation/ethoxycarbonylation of these bromine compounds gave the corresponding carbamic esters 18 and 19, instead of the expected Fcca esters. By lithiation/carboxylation and subsequent esterification, 5, 6, 16 and 17 were converted into the desired 11 and 12. 1\u27-Acetylferrocene-1-carboxylic acid (21) was transformed into oxime 22 and oxime-ester 23. Hydrogenation of this intermediate resulted in formation of Fcca-OMe (24) in very good yield. The structure of the compounds prepared was confirmed by HRMS and spectroscopic analyses

Synthesis and Structure of Geometric Isomers of 1-[(methoxyimino)ethyl]-ferrocene and Methyl 1\u27-[(methoxyimino)ethyl]ferrocene-1-carboxylate

Here we report synthesis, spectral data and single-crystal X-ray molecular and crystal structures of (E)-1-[(methoxyimino)ethyl] ferrocene (2) and (E)-methyl 1\u27-[(methoxyimino)ethyl]ferrocene-1- carboxylate (4). These organometallics are recognized as precursors for optically pure (1- ferrocenylethyl)amine (Fea) and 1\u27-(1-aminoethyl)ferrocene-1-carboxylic acid (Fcca) derivatives. The (E/Z)mixtures of the title compounds 2 and 4 were obtained in ≈90 % yield by the action of methoxyamine hydrochloride on acetylferrocene (1) and 1\u27-acetylferrocene-1-carboxylic acid (3). By means of preparative thin layer chromatography the synthesized compounds were separated into 75 % of (E)-2 and 15 % of (Z)-2, as well as into 68 % of (E)-4 and 22 % of (Z)-4. Crystal structures of the dominant isomers of 2 (two molecules within asymmetric unit) and 4 confirm that both compounds exist in (E)-forms. The ferrocenyl moieties deviate slightly from eclipsed conformation in 2 and 4. The intramolecular C−H···O contact in the C(CH3)−N−OCH3 group (2.670(7) Å in the second molecule of 2 and 2.644(6) Å in 4) can be regarded as a weak intramolecular hydrogen bond. The crystal packings of 2 and 4 are characterized only by van der Waals forces

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

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

Bis- and trisamides derived from 1´-aminoferrocene-1-carboxylic acid and alpha-amino acids : synthesis and conformational analysis

Ferrocene derivatives with one or two achiral and chiral arms based on α-amino acids (Gly, l-Ala, l-Val) attached to the cyclopentadienyl rings were prepared by solution-phase peptide synthesis from N-acetyl- and N-Boc-protected 1′-aminoferrocene-1-carboxylic acids (Boc = tert-butoxycarbonyl). The conformational preference in the solid state of selected examples was elucidated by X-ray crystallography. The chiroptical properties of chiral bis- and trisamides were investigated by circular dichroism (CD) spectroscopy in solution. The conformational preference was studied by NMR and IR spectroscopy, as well as by molecular modeling (DFT). For the bisamides, a conformational library is observed in solution. Increasing the steric bulk of the amino acid side chain disfavors several energetically accessible conformers of bisamides and specific conformers can be selected by changing the environment (type of solvent; solid/solution). For the trisamides, a single conformer is highly stabilized by two intramolecular hydrogen bonds irrespective of the size of the protecting group, the size of the amino acid side chain and the medium

Spectroscopic and theoretical study of asymmetric 1,1'-diaminoferrocene conjugates of alpha-amino acids

The synthesis and characterization of asymmetric 1,1'-diaminoferroceneconjugates of alpha-amino acids Boe-AA-NH-Fn-NH-Ac [AA = Gly (10), Ala(11), D-Ala (12), Val (13), Fn = 1,1'-ferrocenediyl] is reported. Theconformational preferences of these organometallic peptidomimetics insolution are determined experimentally by circular dichroismspectroscopy, IR spectroscopy, and NMR spectroscopy and corroboratedtheoretically by DFT calculations

Bioconjugates of 1'-aminoferrocene-1-carboxylic acid with (S)-3-amino-2-methylpropanoic acid and L-alanine

Formal CH2 insertion in bioconjugates composed of 1′-aminoferrocene-1-carboxylic acid (Fca) and alanine Boc-Ala-Fca-Ala-OCH3 gives Fca bioconjugates with the β-amino acid (S)-3-amino-2-methylpropanoic acid (Aib). The novel homologous conjugates of ferrocene were fully characterized by spectroscopic and analytical methods. NMR, CD and IR spectroscopy in concert with DFT calculations suggest that the formal “L-Ala–to–(S)-β-Aib mutations” can exert ferrocene helix inversion due to the different stereogenic carbon atoms of L-Ala and (S)-β-Aib. Furthermore, the mutation (de-)stabilizes the conserved secondary structure with two intramolecular hydrogen bonds, depending on the “mutation site”. The systematic work presented provides a firm basis for understanding the factors that determine folding in bioconjugates of ferrocene and β-amino acids and will guide the rational design of metallocene peptidomimetics incorporating β-amino acids