A novel synthetic approach toward a poorly explored bioorganometallic consisting of ferrocene-1,1'-diamine bearing structurally and chirally diverse amino acid sequences is reported. Until now, ferrocene-1,1'-diamine was suitable for accommodating only identical amino acid sequences at its N-termini, leading to the symmetrically disubstituted homochiral products stabilized through a 14-membered intramolecular hydrogen-bonded ring as is seen in antiparallel β-sheet peptides. The key step of the novel synthetic pathway is the transformation of Ac-Ala-NH-Fn-COOH (5) (Fn = 1,1'-ferrocenylene) to orthogonally protected Ac-Ala-NH-Fn-NHBoc (7). The spectroscopic analysis (IR, NMR, CD) of the novel compounds, corroborated with DFT studies, suggests the interesting feature of the ferrocene-1,1'-diamine scaffold. The same hydrogen-bonding pattern, i.e. a 14-membered hydrogen-bonded ring, was determined both in solution and in the solid state, thus making them promising, yet simple scaffolds capable of mimicking β-sheet peptides. In vitro screening of potential anticancer activity in Hep G2 human liver carcinoma cells and Hs 578 T human breast cancer cells revealed a cytotoxic pattern for novel compounds (150-500 μM) with significantly decreased cell proliferation.
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.
The synthesis and characterization of asymmetric 1,1′-diaminoferrocene conjugates of R-amino acids Boc-AA-NH-Fn-NH-Ac [AA ) Gly (10), Ala (11), D-Ala (12), Val (13), Fn ) 1,1′-ferrocenediyl] is reported. The conformational preferences of these organometallic peptidomimetics in solution are determined experimentally by circular dichroism spectroscopy, IR spectroscopy, and NMR spectroscopy and corroborated theoretically by DFT calculations.
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