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.

Structurally different ferrocene peptides I-VI exhibit considerable conformational differences. This study has explored the structural properties of VII [Y-AA-Fca-OMe; Y = di-tert-butyl dicarbonate (Boc), acetyl (Ac); AA = L-Ala, D-Ala; Fca = 1Ј-aminoferrocene-1-carboxylic acid] with an exchanged sequence of constituent amino acids relative to VI (Y-Fca-AA-OMe; Y = Boc, Ac; AA = L-Ala, D-Ala). The ferrocene peptides VII were obtained by coupling C-protected Fca with Boc-L-Ala-OH and Boc-D-Ala-OH, respectively. The Boc protecting groups of the obtained conjugates Boc-AA-Fca-OMe (2a, AA = L-Ala; 2b, AA = D-Ala) were converted to sterically less demanding Ac groups to give Ac-AA-Fca-1820 Avance 300 MHz spectrometer in CDCl 3 solutions with Me 4 Si as the internal standard. Double resonance experiments (COSY, NOESY, and HMBC) were performed in order to assist in signal assignment. CD spectra were recorded using a Jasco-810 spectropolarimeter in CH 3 CN. Molar ellipticity coefficients, [θ], are in degrees, concentration, c, is given in molL -1 , and path length, l, is given in cm, to give units for [θ] of deg cm 2 dmol -1 . Computational Details:The starting geometries of 2a and 3a were generated by the MacroModel v9.8 [26] molecular modeling program using several different search methods and force fields. The conformers were fully optimized at the B3LYP/LanL2DZ level of theory. [23] The most stable were reoptimized in chloroform (using IEF-PCM to describe implicit solvent effects) with the B3LYP method and 6-311+G(d,p) basis set. [24] Iron was modeled using the ECP set LanL2DZ. Quantum mechanical calculations were performed with Gaussian 09, v.A.02. [27] Molecules were visualized using GaussView [28] and Chem 3D (CambridgeSoft, Cambridge, MA) programs. The topological analysis of the selected compounds was performed with the AIM2000 program. [29] Boc-AA-Fca-OMe (2a/2b): The syntheses of 2a and 2b were performed according to our recent paper: [9] the fully protected ferrocene amino acid Boc-Fca-OMe [5] (1) was N-deprotected by gaseous HCl in EtOAc to give the hydrochloride salt, which was treated with NEt 3 and coupled with Boc-AA-OH (AA = l-, d-Ala, previously activated by using EDC and HOBt). After standard workup and TLC-purification, Boc-l-Ala-Fca-OMe (2a) and Boc-d-Ala-Fca-OMe (2b) were obtained as orange resins.

Abstract:Our previous studies showed that alteration of dipeptides Y-Fca-Ala-OMe (III) into Y-Ala-Fca-OMe (IV) (Y = Ac, Boc; Fca = 1'-aminoferrocene-1-carboxylic acid) significantly influenced their conformational space. The novel bioconjugates Y-Fca-Pro-OMe (1, Y = Ac; 2, Y = Boc) and Y-Pro-Fca-OMe (3, Y = Boc; 4, Y = Ac) have been prepared in order to investigate the influence of proline, a well-known turn-inducer, on the conformational properties of small organometallic peptides with an exchanged constituent amino acid sequences. For this purpose, peptides 1-4 were subjected to detailed spectroscopic analysis (IR, NMR, CD spectroscopy) in solution. The conformation of peptide 3 in the solid state was determined. Furthermore, the ability of the prepared conjugates to inhibit the growth of estrogen receptor-responsive MCF-7 mammary carcinoma cells and HeLa cervical carcinoma cells was tested.

A series of peptides that contain homo- and heterochiral Ala-Pro sequences attached to the turn-inducing ferrocene-1,1'-diamine scaffold were synthesized. The effects of the backbone chirality and the N-terminal group (Boc/Ac) on the conformational properties of the novel peptidomimetics were thoroughly explored by IR, NMR, and CD spectroscopy and the experimental observations were corroborated by DFT studies in solution. The most stable conformers of the homochiral peptides adopted the interstrand hydrogen-bond patterns, realized through ten- and thirteen-membered rings. The common feature of the most stable conformers of the heterochiral peptides was the adoption of the turn-like structures that feature the simultaneous intra- (seven-membered) and interstrand (sixteen-membered) hydrogen-bonded rings. An exchange of two N-terminal groups had a somewhat larger influence on the distribution of the hydrogen-bond patterns in homochiral than in heterochiral derivatives. The homochiral peptides that contain pyridine moieties as metal coordination sites formed 1:1 complexes with divalent metal ions, which included Zn , Cd , Cu and Fe .

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