John F. Boas

Copper-mediated Amyloid-β Toxicity Is Associated with an Intermolecular Histidine Bridge

Amyloid-β peptide (Aβ) is pivotal to the pathogenesis of Alzheimer disease. Here we report the formation of a toxic Aβ-Cu2+ complex formed via a histidine-bridged dimer, as observed at Cu2+/peptide ratios of >0.6:1 by EPR spectroscopy. The toxicity of the Aβ-Cu2+ complex to cultured primary cortical neurons was attenuated when either the π -or τ-nitrogen of the imidazole side chains of His were methylated, thereby inhibiting formation of the His bridge. Toxicity did not correlate with the ability to form amyloid or perturb the acyl-chain region of a lipid membrane as measured by diphenyl-1,3,5-hexatriene anisotropy, but did correlate with lipid peroxidation and dityrosine formation. 31P magic angle spinning solid-state NMR showed that Aβ and Aβ-Cu2+ complexes interacted at the surface of a lipid membrane. These findings indicate that the generation of the Aβ toxic species is modulated by the Cu2+ concentration and the ability to form an intermolecular His bridge.

Spectroscopy of Naphthalene Diimides and Their Anion Radicals

Naphthalene diimides 1–4 having different N,N-disubstitution undergo single electron reduction processes either chemically or electrochemically to yield the corresponding radical anion in high yield. This study concentrates on 1, bearing pentyl side chains connected through the diimide nitrogens, and compares the results obtained against those bearing isopropyl, propargyl, and phenylalanyl side chains. Compound 1 exhibits mirror image absorption and fluorescence in the near-UV region in CH2Cl2 and dimethylformamide that is typical of monomeric N,N-dialkyl-substituted naphthalene diimides. In toluene, excimer-like emission is observed, which suggests ground-state complexes involving 1 are formed. X-Ray crystallography has been used to characterize 1 in the solid state. Cyclic voltammetry enables the reversible potentials for [NDI]0/– and [NDI]−/2– type processes to be measured. Bulk one-electron reduction of 1–4 is characterized by dramatic changes in the absorption and emission spectra. Additionally, highly structured EPR (electron paramagnetic resonance) signals from dimethylformamide solutions of the radical anions of 1–3 have been obtained and are consistent with coupling between the unpaired electron and the naphthalene diimide nitrogens and hydrogens and the NCH hydrogens of the appropriate side chains. The overall structure of the EPR spectrum is substituent-dependent. These changes in spectroscopic output upon an electronic input may be described as a simple ‘on/off’ switching mechanism with which to apply a ‘bottom-up’ approach to molecular device manufacture.

Heptanuclear iron(III) triethanolamine clusters exhibiting ‘millennium dome’-like topologies and an octanuclear analogue with ground spin states of S = 5/2 and 0, respectively

The synthesis and structural determination of the tripodal triethanolamine (teaH3) based octanuclear cluster [FeIII8O3(O2CCH2CH3)6(tea)(teaH)3(F)3]·0.5MeOH·0.5H2O (1) is reported. The octanuclear core in 1 has only been observed once before in the analogous teaH3 based [Fe8O3(O2CPh)9(tea)(teaH)3]·MeCN cluster and, as observed in that case, magnetic susceptibility measurements on 1 indicate a ground spin state of S = 0. Reaction of the trinuclear complex [FeIII3O(O2CCMe3)6(H2O)3](O2CCMe3) with the tripodal ligands 1-[N,N-bis(2-hydroxyethyl)-amino]-2-propanol (bheapH3) and triethanolamine (teaH3) gives [FeIII7O3(O2CCMe3)9(bheapH)3(H2O)3] (2) and [FeIII7O3(O2CCMe3)9(teaH)3(H2O)3] (3), respectively. The cores in 2 and 3 are dome-like in topology, an architecture unseen in any heptanuclear clusters reported to date. Magnetisation and susceptibility measurements show that clusters 2 and 3 exhibit ground spin states of S = 5/2. Low temperature EPR measurements confirm these ground spin states and yield zero-field splitting parameters of D = 0.28 cm−1 and E/D of 0.21 (for 3).

Systematic study of spin crossover and structure in [Co(terpyRX)2](Y)2 systems (terpyRX = 4'-alkoxy-2,2':6',2''-terpyridine, X = 4, 8, 12, Y = BF4(-), ClO4(-), PF6(-), BPh4(-)).

A family of spin crossover cobalt(II) complexes of the type [Co(terpyRX)(2)](Y)(2) x nH(2)O (X = 4, 8, 12 and Y = BF(4)(-), ClO(4)(-), PF(6)(-), BPh(4)(-)) has been synthesized, whereby the alkyl chain length, RX, and counteranion, Y, have been systematically varied. The structural (single crystal X-ray diffraction) and electronic (magnetic susceptibility, electron paramagnetic resonance (EPR)) properties have been investigated within this family of compounds. Single crystal X-ray diffraction analysis of [Co(terpyR8)(2)](ClO(4))(2), [Co(terpyR8)(2)](BF(4))(2) x H(2)O, and [Co(terpyR4)(2)](PF(6))(2) x 3 H(2)O, at 123 K, revealed compressed octahedral low spin Co(II) environments and showed varying extents of disorder in the alkyl tail portions of the terpyRX ligands. The magnetic and EPR studies were focused on the BF(4)(-) family and, for polycrystalline solid samples, revealed that the spin transition onset temperature (from low to high spin) decreased as the alkyl chain lengthened. EPR studies of polycrystalline powder samples confirmed these results, showing signals only due to the low spin state at the temperatures seen in magnetic measurements. Further to this, simultaneous simulation of the EPR spectra of frozen solutions of [Co(terpyR8)(2)](BF(4))(2) x H(2)O, recorded at S-, X-, and Q-band frequencies, allowed accurate determination of the g and A values of the low spin ground state. The temperature dependence of the polycrystalline powder EPR spectra of this and the R4 and R12 complexes is explained in terms of Jahn-Teller effects using the warped Mexican hat potential energy surface model perturbed by the low symmetry of the ligands. While well recognized in Cu(II) systems, this is one of the few times this approach has been used for Co(II).

Observation of Ferromagnetic Exchange, Spin Crossover, Reductively Induced Oxidation, and Field-Induced Slow Magnetic Relaxation in Monomeric Cobalt Nitroxides

The reaction of [Co(II)(NO3)2]·6H2O with the nitroxide radical, 4-dimethyl-2,2-di(2-pyridyl) oxazolidine-N-oxide (L(•)), produces the mononuclear transition-metal complex [Co(II)(L(•))2](NO3)2 (1), which has been investigated using temperature-dependent magnetic susceptibility, electron paramagnetic resonance (EPR) spectroscopy, electrochemistry, density functional theory (DFT) calculations, and variable-temperature X-ray structure analysis. Magnetic susceptibility measurements and X-ray diffraction (XRD) analysis reveal a central low-spin octahedral Co(2+) ion with both ligands in the neutral radical form (L(•)) forming a linear L(•)···Co(II)···L(•) arrangement. This shows a host of interesting magnetic properties including strong cobalt-radical and radical-radical intramolecular ferromagnetic interactions stabilizing a S = (3)/2 ground state, a thermally induced spin crossover transition above 200 K and field-induced slow magnetic relaxation. This is supported by variable-temperature EPR spectra, which suggest that 1 has a positive D value and nonzero E values, suggesting the possibility of a field-induced transverse anisotropy barrier. DFT calculations support the parallel alignment of the two radical π*NO orbitals with a small orbital overlap leading to radical-radical ferromagnetic interactions while the cobalt-radical interaction is computed to be strong and ferromagnetic. In the high-spin (HS) case, the DFT calculations predict a weak antiferromagnetic cobalt-radical interaction, whereas the radical-radical interaction is computed to be large and ferromagnetic. The monocationic complex [Co(III)(L(-))2](BPh4) (2) is formed by a rare, reductively induced oxidation of the Co center and has been fully characterized by X-ray structure analysis and magnetic measurements revealing a diamagnetic ground state. Electrochemical studies on 1 and 2 revealed common Co-redox intermediates and the proposed mechanism is compared and contrasted with that of the Fe analogues.

(Pro2H+)2(TCNQ.−)2⋅TCNQ: An Amino Acid Derived Semiconductor

Materials based on TCNQ (tetracyanoquinodimethane) derivatives are of particular interest as they offer promise as biodegradable components for the semiconductor industry. TCNQ itself is a classical electron acceptor with an electron affinity of 2.88 eV so that the anionic radical, TCNQC is readily formed by chemical reduction, photoreduction, or electrochemical methods. In the presence of electron donors, the resulting charge-transfer (CT) complexes with TCNQC are characterized by an extensive range of electronic and optical properties. To date, TCNQC materials have been formed in combination with many cations, including metal ions (Na, Mg, Cu, Gd), organometallic complexes (e.g., ferrocene, [Ru(bpy)3] ), as well as some organic cations (Me4N , NMP, TTF). Characterization of these materials yields a wide range of 1) stoichiometries, 9] including fractional charge transfer ratios, 2) morphologies, even with the same cation, although the radical anion consistently forms laminar p-stacked columns, and 3) phases, induced by electrochemical, photochemical, or thermal methods. Interestingly, even though TCNQ itself is a semiconductor, the band gap is greater than 2 eV 12] so that the conductivity of pure TCNQ crystals is quite low. TCNQC based CT complexes generally have a much higher conductivity, approaching even metallic conductivity 12] or superconductivity under certain conditions. Amino acids are key building blocks for polymeric macromolecules, especially proteins. The side-chain functionality includes a variety of polar, non-polar, aromatic, and heteroatoms. Proline (Scheme 1) is unique insofar as it does not contain a primary amino group, instead it has a secondary amine thereby raising the pKa from 9 to > 10.5. [15] Unlike the typical cationic TCNQ complexes, amino acids are not obvious candidates for TCNQ CT complexes. However, there is one report whereby solid TCNQ was ground with four different amino acids with the formation of a CT product indicated by IR spectroscopy. Here we report the preparation and characterization of a novel bioorganic TCNQ material (Pro2H )2(TCNQC )2·TCNQ (ProTCNQ), formed as a CT compound between neutral l-proline and TCNQ. Water was found to be necessary to provide the proton and the redox balance achieved through the oxidation of water (see Supporting Information, Section S3). Subsequently, rational methods of synthesis were introduced. An extensive range of physicochemical methods has been employed to characterize this new biomaterial. This is the first member of a new class of CT biomaterials derived from amino acids with TCNQ. Synthesis of the ProTCNQ complex was achieved using four different synthetic routes involving either TCNQ or LiTCNQ as a starting material (Section S1). Astonishingly, all methods resulted in the same product, which suggests that the stoichiometry found for ProTCNQ is thermodynamically favored. Dark blue, single crystals of ProTCNQ were obtained by diffusion of diethyl ether into a methanol solution of l-prolineH·BF4 [13a] and LiTCNQ. The asymmetric unit contains two crystallographically independent proline residues and three halves of TCNQ species (Figure 1a, namely TCNQ-A, TCNQ-B, and TCNQ-C, respectively). From the analysis of the mean bond lengths for each TCNQ (Table S1), TCNQ-A and TCNQ-C are regarded as TCNQC radical anions, whereas TCNQ-B is a neutral TCNQ molecule. The structure consists of alternating layers of proline cations and TCNQ moieties (Figure 1b). In each case, the planar TCNQ molecules form three separate 1D chains defined by weak H-bonding interactions between CN and H groups of each TCNQ (Figure 1c). These TCNQ chains run parallel to the b axis (the TCNQ molecules themselves lie parallel to the ab plane), and stack along the c axis to create a 2D layer (Figure 1b). There are strong p–p interactions between the chains containing the TCNQ-A and TCNQ-C Scheme 1. Molecular structure of proline (left) and TCNQ (right).

Detailed voltammetric and EPR study of protonation reactions accompanying the one-electron reduction of Keggin-type polyoxometalates, [XVVM11O40]4− (X = P, As; M = Mo, W) in acetonitrile

The one electron electrochemical reduction of vanadium(V) substituted-Keggin type polyoxometalate anions [XV(V)M(11)O(40)](4-) (XV(V)M(11)) where X = P, As; M = Mo or W has been investigated in CH(3)CN as a function of acid concentration. EPR studies confirm that the product is the highly basic and hence readily protonated V(IV), (XV(IV)M(11)), species. In the absence of acid or in the presence of a large concentration excess, the V(V/IV) redox couple gives one well defined chemically and electrochemically reversible process under conditions of cyclic voltammetry. In contrast, three well resolved V(V/IV) processes are observed in the presence of a moderate concentration of acid in the case of XV(V)Mo(11) but only two with XV(V)W(11). NMR and EPR spectra have been obtained as a function of acid concentration when the polyoxometalate anions are in the V(V) and V(IV) oxidation levels respectively. All voltammetric and spectroscopic data indicate that protonation reactions are coupled to the V(V) and V(IV) redox chemistry but that the reduced V(IV) state is much more basic than the V(V) one and that (XV(IV)Mo(11)) is more basic than (XV(IV)W(11)). Digital simulations of voltammograms for reduction of XV(V)Mo(11) and XV(V)W(11) have been undertaken in CH(3)CN as a function of acid concentration in order to define the thermodynamics and kinetics associated with the V(V/IV) process and the equilibrium constants that accompany the coupled acid-base chemistry. EPR spectra allow an estimation of the relative concentrations of protonated species present in frozen glasses derived from one-electron bulk electrolysis and also allow inferences to be drawn on their nature. This study provides a far more detailed analysis of the coupling of proton and electron transfer than previously available.

Interpretation of electron spin resonance spectra due to some B12-dependent enzyme reactions

Previous studies by a number of authors have shown that during a number of B12-dependent enzyme reactions, e.g., catalysis of amino-2,1-propanol to propionaldehyde in the presence of ethanolamine ammonia lyase as reported by Babior et al., a very characteristic e.s.r. spectrum is observed. It consists of a broad line at g∼ 2.3 and a pair of lines in the intensity ratio of approximately 2:1, split by 7–14 mT, centred about g= 2. Schepler et al. have given a partial explanation for this and four other similar results, basing their interpretation on isotropic exchange coupling between a radical and the cobalt (II) from B12. In this paper we have interpreted the results on the basis of a coupling model which includes both isotropic exchange and dipolar interactions, and which represents a logical extension of previous work of two of the the authors on dissimilar ion coupling. The presence of dipolar coupling brings about an important improvement in the computer simulated lineshapes for the “radical” part of the spectrum, especially for ethanolamine ammonia lyase. The spectra are also sensitive to the sign of the exchange coupling when second order effects are included in the line positions and, more particularly, the intensities. From comparison between computed and experimental spectra, it is concluded that a lower limit for the cobalt (II)-radical separation of 10 A exists in all cases and that it is in the range 10–12 A for ethanolamine ammonia lyase. Clearly this new information regarding distance must be borne in mind in the development of models for the reactions of such enzyme–substrate–coenzyme systems.

Preparation and structure of bis(tetraphenylarsonium) trans-aquatetracyanonitridotechnetate(V) pentahydrate. ESR studies of the [TcN(CN)4(OH2)]2-/[TcNCl4]-system

Abstract The reaction of (AsPh4)[TcNCl4] with KCN and added AsPh4Cl in CH3CN/H2O yields crystals of (AsPh4)2[TcN(CN)4(OH2)]·5H2O (1). The complex crystallises in the monoclinic space group P21/n with a=17.107(5), b=19.965(7), c=15.473(5)A, β= 101.70(2)° and Z=4. Refinement with 3212 data measured with Cu Kα radiation converged at R= 0.065. The geometry of the anion is distorted octahedral with a water molecule coordinated trans to the nitrido ligand (TcOH2, 2.56(1) A). The TcN distance is 1.60(1) A. ESR studies have established the presence of two paramagnetic intermediates in the conversion of [TcN(CN)4(OH2)]2− to [TcNCl]4− in HCl solutions.

Histidine 14 Modulates Membrane Binding and Neurotoxicity of the Alzheimer's Disease Amyloid-β Peptide

Amyloid-beta peptide (Abeta) toxicity is thought to be responsible for the neurodegeneration associated with Alzheimers disease. While the mechanism(s) that modulate this toxicity are still widely debated, it has previously been demonstrated that modifications to the three histidine residues (6, 13, and 14) of Abeta are able to modulate the toxicity. Therefore to further elucidate the potential role of the histidine (H) residues in Abeta toxicity, we synthesized Abeta peptides with single alanine substitutions for each of the three histidine residues and ascertained how these substitutions affect peptide aggregation, metal binding, redox chemistry, and cell membrane interactions, factors which have previously been shown to modulate Abeta toxicity. Abeta{42} H13A and Abeta{42} H6A modified peptides were able to induce significant cell toxicity in primary cortical cell cultures at levels similar to the wild-type peptide. However, Abeta{42} H14A did not induce any measurable toxicity in the same cultures. This lack of toxicity correlated with the inability of the Abeta{42} H14A to bind to cell membranes. The interaction of Abeta with cell membranes has previously been shown to be dependent on electrostatic interactions between Abeta and the negatively charged head group of phosphatidylserine. Our data suggests that it is the imidazole sidechain of histidine 14 that modulates this interaction and strategies inhibiting this interaction may have therapeutic potential for Alzheimers disease.