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A new ferrocenoyl tetrapeptide, Fc-Gly-Gly-Tyr-Arg-OH, has been synthesized, which acts as an effective competitive inhibitor to papain, with a K(i) of 9 microM at pH 6.2. The electrochemical potential of the ferrocenoyl moiety is influenced by papain binding, resulting in a small cathodic shift of 30 mV.
The Pd-catalyzed Sonogashira coupling of ferrocene alkyne derivatives as metal probes to iodophenylalanine containing peptides is described. 4-Iodophenylalanine was incorporated into dipeptides and the neuropeptide [Leu5]-enkephalin (Enk) by solid phase peptide synthesis, thereby creating a functional group suitable for the Sonogashira coupling. The reaction with two different ferrocene alkynes resulted in the corresponding ferrocene-labeled derivatives, which were obtained in good yield and purity. All new compounds were comprehensively characterized, including elemental analysis, 1D and 2D NMR, EI-, FAB- or ESI-MS, IR and UV-vis spectroscopy, and electrochemistry of the ferrocene label. Unlike well-established conjugation methods for peptide side chains such as lysine and cystein, the phenyl group in Phe is not readily available for derivatization. This work presents a versatile procedure for the regioselective introduction of an organometallic label into biologically relevant peptides as exemplified for enkephalin.
A series of ferrocene-containing collagen models Fc-CO-(Pro-Hyp-Gly)n-Cys (n = 4 (1), 6 (2), 7 (3), 8 (4), 9 (5)) were synthesized by solid-phase synthesis. Biophysical studies using circular dichroism (CD) show that these collagen analogues form triple-helical conformations, and the peptides showed a range of thermal stabilities ((T(m)), 38-74 degrees C). Results also indicate that the ferrocene (Fc)-labeled collagen models possesses a higher triple-helical propensity than the unlabeled collagen models as demonstrated by the higher melting temperatures and thermodynamic parameters, and we conclude that the Fc group at the N-terminal position of the peptide strands increases the stability of the triple helix.
A series of ferrocenyl conjugates to fatty acids have been designed and synthesized to establish the key properties required for use in biomolecular binding studies. Amperometric detection of the ferrocene conjugates was sought in the region of 0.3 V (vs Ag/AgCl) for use in protein/blood solutions. Different linkers and solubilizing moieties were incorporated to produce a conjugate with optimal electrochemical properties. In electrochemical studies, the linker directly attached to the ferrocene was found to affect significantly the E(1/2) value and the stability of the ferrocenium cation. Ester-linked ferrocene conjugates had E(1/2) ranging from +400 to +410 mV, while amide-linked compounds ranged from +350 to +370 mV and the amines +260 to +270 mV. Folding of long-chain substituents around the ferrocene, also significantly affected by the choice of linker, was inferred as a secondary effect that increased E(1/2). The stability of the ferrocenium cation decreased systematically as E(1/2) increased. Disubstituted ferrocene ester and amide conjugates, with oxidation potentials of +640 and +570 mV, respectively, showed only a barely discernible reduction wave in cyclic voltammetry at 50 mV/s. Electrochemical measurements identified two lead compounds with the common structural characteristics of an amide and carbamate linker (compounds 17 and 21) with a C(11) fatty acid chain attached. It is envisaged that such molecules can be used to mimic and study the biomolecular binding interaction between fatty acids and molecules such as human serum albumin.
The development of electrochemical probes useful for investigating the occupancy by other molecules of sites on complex proteins such as human serum albumin (HSA) is described. Ferrocenyl-(oxoethylene)-fatty acid compounds of different fatty acid chain length probed different binding sites on HSA. The interaction could be changed from one primarily with a drug binding site, when the probe was ferrocene methanol, to one predominantly with medium-chain fatty acid binding sites, by adding an (oxoethylene)-fatty acid substituents. Finally, the interaction could be changed to one interacting primarily with high-affinity long-chain fatty acid binding sites, as the fatty acid chain length in ferrocene-(oxoethylene)-fatty acid molecules increased. These results strongly implied that the binding could be further tailored by relatively simple modifications to the probe, for example, by changing the balance of hydrophobicity and hydrophilicity. The possibility of a procedure using mass-produced electrochemical cells to determine the fractional occupancy of different sites on HSA is demonstrated.
We report a novel synthetic cysteine oxidase consisting of a ferrocene-beta-cyclodextrin conjugate in which the ferrocene moiety is bound to the secondary hydroxyl side of the cyclodextrin cavity through an ethylenediamine linker. Cysteine oxidation occurs after the ferrocene group is electrochemically oxidized to the ferricinium form, and this generates a voltammetric electrocatalytic wave, the magnitude of which is related to the rate constant for cysteine oxidation. Comparison of cysteine oxidation rates for the primary and secondary beta-cyclodextrin derivatives (105 and 1470 M-1 s-1, respectively) shows that the secondary derivatives are more effective synthetic enzymes. Substrate selectivity of the secondary derivative is demonstrated by comparison of oxidation rates for cysteine (1470 M-1 s-1) and glutathione (260 M-1 s-1) at pH 7.0. The rate constant for cysteine oxidation was 3-fold higher at pH 8.0. With a constant synthetic enzyme concentration, electrocatalytic limiting currents increased linearly with increasing cysteine concentration to a maximum at 6 mM cysteine; above this concentration, the current decreased significantly. These and other results suggest that product inhibition of the catalytic cycle occurs as a result of cystine binding more strongly to the cyclodextrin than cysteine.
The synthesis and single-channel characterization of two redox-active C-terminal derivatives of alamethicin are herein described. The reduced [Fe(II)] forms of ferrocenoyl-alamethicin (Fc-ALM) and 1'-carboxyferrocenoyl-alamethicin (cFc-ALM) are shown to form voltage-dependent ion channels at cis positive potentials in planar lipid bilayers (PLB) with conductance properties similar to those of alamethicin. In situ oxidation of Fc-ALM [to Fe(III)] in the PLB apparatus causes a time-dependent elimination of channel openings, which can be restored by an increase in the transbilayer potential. In contrast, oxidation of cFc-ALM leads to the formation of shorter-lived channels. Pretreatment of the ferrocenoyl peptides with oxidizing agent alters their single-channel properties in a qualitatively similar manner, establishing that the changes in channel properties in the presence of oxidizing agents are due specifically to ferrocenoyl oxidation. We suggest that the redox sensitivity of these ferrocene-containing ion channels may be governed by a combination of the following factors: (1) changes in hydrophobicity; (2) alteration of peptide molecular dipole; and (3) alterations in tendencies toward self-association. However, oxidation induced changes in peptide conformation cannot be ruled out. Our results provide evidence that it is possible to engineer channel-forming peptides that respond to specific changes in the chemical environment.
1. The absorption changes associated with the formation of P+QBred (QBred stands for the semiquinone state of the secondary quinone acceptor) were investigated in chromatophores of Rhodobacter capsulatus. Marked modifications of the semiquinone spectrum were observed when the pH was lowered from 7 to 5. These modifications match those expected for a complete conversion of QBred from the anionic state QB- at pH 7 to the neutral protonated state QBH at pH 5. Similar modifications were observed in chromatophores from Rb. sphaeroides, but not in purified reaction centers from Rb. capsulatus, suggesting that the environment of the reaction center (native membrane vs detergent micelle) is the crucial parameter. 2. The recombination reaction P+QBred --> PQB was investigated as a function of pH. No particular kinetic heterogeneity was observed at low pH, showing that QBH remains mostly bound to the reaction center. The rate constant reaches a minimum value of 0.08 s-1 at pH 6, suggesting that the direct route for recombination prevails in chromatophores below this pH, instead of the usual pathway via QA-. 3. The proton uptake caused by QBred is about 1 below pH 7 and decreases at higher pH. It is suggested that the pH dependence of the conversion of QB- to QBH, occurring in a range where the uptake is constant, cannot be accommodated by a purely electrostatic model, but probably involves a conformational change. 4. The kinetics of the electron-transfer reaction QA-QB-->QAQBred were investigated. A 2-fold acceleration was observed between pH 7 and pH 5 (t1/2 approximately 30 and 15 microseconds, respectively). A fast (<<10 microseconds) unresolved phase appears to be present at both pHs. The second electron-transfer QA-QBred-->QAQBH2 proceeds with a similar rate as the first electron transfer (15-30 microseconds phase). Consequences for the rate-limiting step are discussed. 5. The carotenoid shift, indicative of the membrane potential, displays a rising phase concomitant with the QA-QB-->QAQBred electron transfer. Its relative extent is markedly increased at pH 5, with part of the kinetics occurring during the unresolved fast phase. 6. The extent of the electrochromic shift of bacteriopheophytin around 750 nm associated with formation of QBred decreases toward acidic pH, reflecting the charge compensation due to proton uptake and the formation of neutral QBH.
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A series of ferrocenyl surfactants was tested as model compounds to study electron transfer reactions involving structural Fe(III) in clay minerals. The surfactants contain trimethylammonium headgroups, ferrocene tail groups, and intervening hydrocarbon chain lengths of one, six, or 11 carbons. Two factors considered to be decisive for electron transfer were addressed: (1) physical access of the surfactant ferrocene to the reactive sites through hexagonal holes in the clay lattice by X-ray diffraction (XRD) and small-angle X-ray scattering (SAXS) and (2) thermodynamic favorability of the overall oxidation/reduction reaction based on experimentally determined oxidation/reduction potentials. In suspensions of clay with the longer chain surfactants, (ferrocenylhexyl)trimethylammonim (FHTMA+) and (ferrocenylundecyl)trimethylammonium (FUTMA+), where electron transfer may be expected to be favored by both factors, physical accessibility, and thermodynamic favorability, ferroecene oxidation was observed by diffuse reflectance infrared spectroscopy (DRIFT), ultraviolet-visible spectroscopy (UV-vis), and visual color changes. In contrast, the shorter chain length surfactant, (ferrocenylmethyl)trimethylammonium (FMTMA+), did not participate in electron transfer with the clay, as substantiated by UV-vis and no visible color changes. Rigid conformation and/or higher oxidation/reduction potential than clay Fe can accountforthe lack of reaction. The utility and limitations of using these surfactants as model compounds is discussed.
For the recognition of all but the simplest naturally occurring molecules, electrochemical sensors based on ferrocene will certainly require chiral centers. To advance the necessary chemistry, this work describes the synthesis and properties of ferrocene derivatives of enantiomerically pure amino acids, peptides, and other chiral amines. Ferrocene aldehyde is condensed with amino acid esters to yield the corresponding Schiff bases 2, which are reduced by NaBH4 in methanol to the ferrocene methyl amino acids 3. An X-ray single-crystal analysis was carried out on the phenylalanine derivative 3a (monoclinic space group P2(1), a = 10.301(1) A, b = 9.647(1) A, c = 18.479(2) A, beta = 102.98(2) degrees, Z = 4). Further peptide chemistry at the C terminus proceeds smoothly as demonstrated by the synthesis of the ferrocene labeled dipeptide Fc-CH2-Phe-Gly-OCH3 5 (Fc = ferrocenyl ((eta-C5H4)Fe(eta-C5H5))). We also report the synthesis of the C,N-bis-ferrocene labeled tripeptide Phe-Ala-Leu and its electrochemical characterization. Starting from the enantiomerically pure ferrocene derivative 9, which was synthesized from ferrocene aldehyde and L-1-amino-ethylbenzene, two diastereomers 10 were obtained by peptide coupling with N-Boc protected D- and L-alanine. There was, however, only very little diastereomeric induction if 0.5 equiv of a racemic mixture of alanine were used. This suggests that amino acid activation rather than coupling is the rate-determining step. A combination of NOESY (nuclear Overhauser effect spectroscopy) spectra and molecular modeling furnished detailed insights into the solution structures of 3, 9, and 10 and was used to rationalize their different reactivity.
The novel ferrocenyl ligand rac-1,6-diferrocenyl-N,N'-bis(2-hydroxypropyl)-2,5-diazahexane (1, H(2)L) was synthesized from ferrocenylcarboxaldehyde and ethylenediamine followed by the reduction of the Schiff base with LiAlH(4) and subsequent N-alkylation with 1,2-propyleneoxide. The dianion of H(2)L reacted with [ReO(PPh(3))(2)Cl(3)], and the product was treated with NH(4)PF(6) to afford the complex [ReO(L-N(2)O(2))PPh(3)]PF(6) (2). Both the ferrocenyl ligand and the complex were characterized in solution by NMR spectroscopy and in the solid state by single-crystal X-ray diffraction studies. NMR investigations reveal two solvent-dependent isomers for the ferrocenyl ligand in solution of which the major form is the more ordered one. The cation of 2 displays a nonsymmetrically coordinated N(2)O(2) ligand.
The use of 3-aminopyrazole derivatives as beta-sheet templates is investigated using a series of ferrocenoyl (Fc)-dipeptides (Fc-Gly(2)-OEt, Fc-Ala(2)-OBzl, Fc-Leu-Phe-OMe, Fc-Val-Phe-OMe, Fc-Phe(2)-OMe, Fc-Leu(2)-OMe, Fc-Val(2)-OMe). The synthesis and full characterization are reported. The solid-state structures of Fc-Gly(2)-OMe and Fc-Leu-Phe-OMe show extensive hydrogen bonding of the podand peptide substituents, resulting in the formation of supramolecular Fc-dipeptide assemblies. For Fc-Gly(2)-OMe, this can be described as a parallel beta-sheet, whereas intermolecular interactions in Fc-Leu-Phe-OMe result in the formation of supramolecular helical structures. The saturation titrations of Fc-dipeptides with 3-amino-5-methylpyrazole (3-AMP) and 3-trifluoroacetylamido-5-methylpyrazole (3-TFAc-AMP) show a 1:1 interaction of the Fc-peptide with the aminopyrazole derivatives. IR measurements in solution confirm binding to the top face of the Fc-dipeptide and the involvement of the Fc-C=O and the ester C=O groups in establishing H-bonding interactions with the 3-TFAc-AMP. However, binding constants in chloroform are low and range from 8 to 27 M(-1), which correspond to binding energies of 5-7 kJ mol(-1). In higher polarity solvents, such as acetonitrile or acetone, the binding constants are below 5 M(-1), emphasizing the limited utility of 3-AMP derivatives as beta-sheet templates. Electrochemical measurements confirm the weak interactions between the various Fc-dipeptides and 3-TFAc-AMP. Typical shifts in the redox potential of the Fc moiety are in the range 0-20 mV. Attempts to modify 3-AMP at the 3-position by carbodiimide coupling with amino acid derivatives and, thus, enhance the binding to the Fc-peptides resulted in 2-amino acid substituted 3-AMP derivatives. Substitution at the 2-position blocks the binding site, and no interactions with Fc-dipeptides are observed.
We report the synthesis, structural and spectroscopic characterization, and magnetic and electrochemical studies of a series of iron(II) complexes of the pyridyl-appended diazacyclooctane ligand L(8)py(2), including several that model the square-pyramidal [Fe(II)(N(his))(4)(S(cys))] structure of the reduced active site of the non-heme iron enzyme superoxide reductase. Combination of L(8)py(2) with FeCl(2) provides [L(8)py(2)FeCl(2)] (1), which contains a trigonal-prismatic hexacoordinate iron(II) center, whereas a parallel reaction using [Fe(H(2)O)(6)](BF(4))(2) provides [L(8)py(2)Fe(FBF(3))]BF(4) (2), a novel BF(4)(-)-ligated square-pyramidal iron(II) complex. Substitution of the BF(4)(-) ligand in 2 with formate or acetate ions affords distorted pentacoordinate [L(8)py(2)Fe(O(2)CH)]BF(4) (3) and [L(8)py(2)Fe(O(2)CCH(3))]BF(4) (4), respectively. Models of the superoxide reductase active site are prepared upon reaction of 2 with sodium salts of aromatic and aliphatic thiolates. These model complexes include [L(8)py(2)Fe(SC(6)H(4)-p-CH(3))]BF(4) (5), [L(8)py(2)Fe(SC(6)H(4)-m-CH(3))]BF(4) (6), and [L(8)py(2)Fe(SC(6)H(11))]BF(4) (7). X-ray crystallographic studies confirm that the iron(II)-thiolate complexes model the square-pyramidal geometry and N(4)S donor set of the reduced active site of superoxide reductase. The iron(II)-thiolate complexes are high spin (S = 2), and their solutions are yellow in color because of multiple charge-transfer transitions that occur between 300 and 425 nm. The ambient temperature cyclic voltammograms of the iron(II)-thiolate complexes contain irreversible oxidation waves with anodic peak potentials that correlate with the relative electron donating abilities of the thiolate ligands. This electrochemical irreversibility is attributed to the bimolecular generation of disulfides from the electrochemically generated iron(III)-thiolate species.
Two new charge-transfer hybrids with one or two ferrocenyl units covalently attached to a hexamolybdate cluster through an extended pi-conjugated bridge have been prepared using Pd-catalyzed coupling reactions on monoiodo- or diiodo-functionalized cluster substrates in over 60% yields. These hybrids have been characterized by (1)H NMR, FTIR, electrospray ionization mass spectrometry, and X-ray diffraction. The electronic spectra of these hybrids show a broad absorption tail extending beyond 550 nm, indicating the existence of charge-transfer transition from the ferrocenyl donor to the cluster acceptor. The observation of the clear charge-transfer transition indicates the contribution of charge-transfer resonance to the ground state in both 2a and 2b even though the donor-acceptor separation distance of 11.29 A is rather long, signaling a through-bond charge-transfer nature made possible by the organic pi-conjugated bridge. Cyclic voltammetry studies reveal a one-electron oxidation wave and a one-electron reduction wave for the hybrid with one ferrocenyl unit. For the one with two ferrocenyl units, a lower reduction potential and a two-electron oxidation wave are observed, indicating negligible electronic interactions between the two ferrocenyl units.
Cyclodextrin cavities have been grafted into a layered metal hydroxide to create hydrophobic nanopockets within the galleries of the inorganic solid. Neutral ferrocene molecules can be included within the grafted cavities by partitioning from a polar solvent to generate a new organometallic-organic-inorganic hybrid. The included ferrocene has been characterized by electronic and Raman spectroscopy. The capability of the cyclodextrin-functionalized solid to separate hydrophobic and hydrophilic derivatives of ferrocene is demonstrated.