Mechanistic studies of Cu(II) binding to amyloid-beta peptides and the fluorescence and redox behaviors of the resulting complexes

Due in large part to the lack of crystal structures of the amyloid-beta (Abeta) peptide and its complexes with Cu(II), Fe(II), and Zn(II), characterization of the metal-Abeta complex has been difficult. In this work, we investigated the complexation of Cu(II) by Abeta through tandem use of fluorescence and electron paramagnetic resonance (EPR) spectroscopies. EPR experiments indicate that Cu(II) bound to Abeta can be reduced to Cu(I) using sodium borohydride and that both Abeta-Cu(II) and Abeta-Cu(I) are chemically stable. Upon reduction of Cu(II) to Cu(I), the Abeta fluorescence, commonly reported to be quenched upon Abeta-Cu(II) complex formation, can be regenerated. The absence of the characteristic tyrosinate peak in the absorption spectra of Abeta-Cu(II) complexes provides evidence that the sole tyrosine residue in Abeta is not one of the four equatorial ligands bound to Cu(II), but remains close to the metal center, and its fluorescence is sensitive to the copper oxidation state and perturbations in the coordination sphere. Further analysis of the quenching and Cu(II) binding behaviors at different Cu(II) concentrations and in the presence of the competing ligand glycine offers evidence supporting the operation of two binding regimes which demonstrate different levels of fluorescence recovery upon addition of the reducing agent. We provide results that suggest the fluorescence quenching is likely caused by charge transfer processes. Thus, by using tyrosine to probe the coordination site, fluorescence spectroscopy provides valuable mechanistic insights into the oxidation state of copper ions bound to Abeta, the binding heterogeneity, and the influence of solution conditions on complex formation.     

Electrostatic properties of aqueous salt solution interfaces: a comparison of polarizable and nonpolarizable ion models

The effects of ion force field polarizability on the interfacial electrostatic properties of approximately 1 M aqueous solutions of NaCl, CsCl, and NaI are investigated using molecular dynamics simulations employing both nonpolarizable and Drude-polarizable ion sets. Differences in computed depth-dependent orientational distributions, "permanent" and induced dipole and quadrupole moment profiles, and interfacial potentials are obtained for both ion sets to further elucidate how ion polarizability affects interfacial electrostatic properties among the various salts relative to pure water. We observe that the orientations and induced dipoles of water molecules are more strongly perturbed in the presence of polarizable ions via a stronger ionic double layer effect arising from greater charge separation. Both anions and cations exhibit enhanced induced dipole moments and strong z alignment in the vicinity of the Gibbs dividing surface (GDS) with the magnitude of the anion induced dipoles being nearly an order of magnitude larger than those of the cations and directed into the vapor phase. Depth-dependent profiles for the trace and z z components of the water molecular quadrupole moment tensors reveal 40% larger quadrupole moments in the bulk phase relative to the vapor which mimics a similar observed 40% increase in the average water dipole moment. Across the GDS, the water molecular quadrupole moments increase nonmonotonically (in contrast to the water dipoles) and exhibit a locally reduced contribution just below the surface due to both orientational and polarization effects. Computed interfacial potentials for the nonpolarizable salts yield values 20-60 mV more positive than pure water and increase by an additional 30-100 mV when ion polarizability is included. A rigorous decomposition of the total interfacial potential into ion monopole, water and ion dipole, and water quadrupole components reveals that a very strong, positive ion monopole contribution is offset by negative contributions from all other potential sources. Water quadrupole components modulated by the water density contribute significantly to the observed interfacial potential increments and almost entirely explain observed differences in the interfacial potentials for the two chloride salts. By lumping all remaining nonquadrupole interfacial potential contributions into a single "effective" dipole potential, we observe that the ratio of quadrupole to "effective" dipole contributions range from 2:1 in CsCl to 1:1.5 in NaI, suggesting that both contributions are comparably important in determining the interfacial potential increments. We also find that oscillations in the quadrupole potential in the double layer region are opposite in sign and partially cancel those of the "effective" dipole potential.     

Asymmetric lithiation-substitution of amines involving rearrangement of borates

Asymmetric lithiation of substituted benzylamines, N-Boc-pyrrolidine, or N-Boc-indoline using Beak's methodology was followed by electrophilic quench with trialkylboranes. The resulting borate intermediates rearrange with concomitant C-N bond breakage to give, after oxidation, chiral secondary alcohols with high enantioselectivity.     

Stereoselective Construction of Tertiary Homoallyl Alcohols and Ethers by Nucleophilic Substitution at Quaternary Carbon Stereocenters

An efficient method for the stereoselective construction of tertiary C−O bonds via a stereoinvertive nucleophilic substitution at the quaternary carbon stereocenter of cyclopropyl carbinol derivatives using water, alcohols and phenols as nucleophiles has been developed. This substitution reaction proceeds under mild conditions and tolerates several functional groups, providing a new access to the stereoselective formation of highly congested tertiary homoallyl alcohols and ethers.     

Enhanced Adsorption of Epoxy-Functional Nanoparticles onto Stainless Steel Significantly Reduces Friction in Tribological Studies

Epoxy-functional sterically-stabilized diblock copolymer nanoparticles (ca. 27 nm) are prepared via RAFT dispersion polymerization in mineral oil. Nanoparticle adsorption onto stainless steel is examined using a quartz crystal microbalance. Incorporating epoxy groups within the steric stabilizer chains results in a two-fold increase in the adsorbed amount, Γ, at 20 °C (7.6 mg m⁻²) compared to epoxy-core functional nanoparticles (3.7 mg m⁻²) or non-functional nanoparticles (3.8 mg m⁻²). A larger difference in Γ is observed at 40 °C; this suggests chemical adsorption of the nanoparticles rather than merely physical adsorption. A remarkable near five-fold increase in Γ is observed for ca. 50 nm epoxy-functional nanoparticles compared to non-functional nanoparticles (31.3 vs. 6.4 mg m⁻², respectively). Tribological studies confirm that chemical adsorption of the latter epoxy-functional nanoparticles leads to a significant reduction in friction between 60 °C and 120 °C.     

Solvent Induced Conversion of a Self-Assembled Gyrobifastigium to a Barrel and Encapsulation of Zinc-Phthalocyanine within the Barrel for Enhanced Photodynamic Therapy

A rare gyrobifastigium architecture ( GB ) was constructed by self-assembly of a tetradentate donor ( L ) with Pd^II acceptor in DMSO. The GB was converted to its isomeric tetragonal barrel ( MB ) upon treatment with water. The hydrophobic cavity of MB has been explored for the encapsulation of zinc-phthalocyanine ( ZnPc ), which is an excellent photosensitizer for photodynamic therapy (PDT). However, the poor water-solubility and aggregation tendency are the main reasons for the suboptimal PDT performance of free ZnPc in the aqueous medium. Effective solubilization of ZnPc in an aqueous medium was achieved by encapsulating it in the cavity of MB . The inclusion complex ( ZnPc⊂MB ) showed enhanced singlet oxygen generation in water. Higher cellular uptake and anticancer activity of the ZnPc⊂MB compared to free ZnPc on HeLa cells indicate that encapsulation of ZnPc in an aqueous host is a potential strategy for enhancement of its PDT activity in water.     

Coordination polymers from the self-assembly of silver(I) salts and two nonlinear aliphatic dinitrile ligands, cis-1,3-cyclopentanedicarbonitrile and cis-1,3-bis(cyanomethyl)cyclopentane: synthesis, structures, and photoluminescent properties

Six coordination polymers with aliphatic dinitrile ligands, {[Ag(cpdcn)2]ClO4}n (6a), {[Ag(cpdcn)2]PF6}n (6b), {[Ag(cpdcn)2]SbF6}n (6c, cpdcn = cis-1,3-cyclopentanedicarbonitrile), {[Ag(bcmcp)2] ClO4}n (7a), {[Ag(bcmcp)2]PF6}n (7b), {[Ag(bcmcp)2]SbF6}n, (7c, bcmcp = cis-1,3-bis(cyanomethyl)cyclopentane) have been synthesized and structurally characterized by IR spectroscopy, differential scanning calorimetry (DSC), thermogravimetric analysis (TGA) and X-ray crystallography. Both ligands used in this study are meso-compounds; while the ligand cpdcn is structurally rigid, the ligand bcmcp has greater conformational flexibility. X-ray crystallography has revealed that structures 6a-c consist of chiral 1D-polymers. The structure of complexes 7a and 7b are best described as a 2D chiral (4,4) square mesh with 3-fold parallel interpenetration. Surprisingly, complex 7c was characterized to be an achiral 1D coordination polymer. The synthesis of the ligands, IR spectra of the free and coordinated CN groups, DSC and TGA, and the photoluminescent properties of complexes 6a-c and 7a-c are also discussed.     

Synthesis, separation, and circularly polarized luminescence studies of enantiomers of iridium(III) luminophores

A family of heteroleptic (C;N)2Ir(acac) and homoleptic fac-Ir(C;N)3 complexes have been synthesized and their photophysical properties studied (where C;N = a substituted 2-phenylpyridine and acac = acetylacetonate). The neutral Delta and Lambda complexes were separated with greater than 95% enantiomeric purity by chiral supercritical fluid chromatography, and the solution circular dichroism and circularly polarized luminescence spectra for each of the enantio-enriched iridium complexes were obtained. The experimentally measured emission dissymmetries (gem) for this series compared well with predicted values provided by time-dependent density functional theory calculations. The discovered trend further showed a correlation with the dissymmetries of ionic, enantiopure hemicage compounds of Ru(II) and Zn(II), thus demonstrating the applicability of the model for predicting emission dissymmetry values across a wide range of complexes.     

Origin and control of superlinear polarizability scaling in chemical potential equalization methods

Many common chemical potential equalization (muEq) methods are known to suffer from a superlinear scaling of the polarizability with increasing molecular size that interferes with model transferability and prevents the straightforward application of these methods to large, biochemically relevant molecules. In the present work, we systematically investigate the origins of this scaling and the mechanisms whereby some existing methods successfully temper the scaling. We demonstrate several types of topological charge constraints distinct from the usual single molecular charge constraint that can successfully achieve linear polarizability scaling in atomic charge based equilibration models. We find the use of recently employed charge conservation constraints tied to small molecular units to be an effective and practical approach for modulating the polarizability scaling in atomic muEq schemes. We also analyze the scaling behavior of several muEq schemes in the bond representation and derive closed-form expressions for the polarizability scaling in a linear atomic chain model; for a single molecular charge constraint these expressions demonstrate a cubic dependence of the polarizability on molecular size compared with linear scaling obtainable in the case of the atom-atom charge transfer (AACT) and split-charge equilibration (SQE) schemes. Application of our results to the trans N-alkane series reveals that in certain situations, the AACT and SQE schemes can become unstable due to an indefinite Hessian matrix. Consequently, we discuss sufficient criteria for ensuring stability within these schemes.     

Synthesis of some oxazolyl ‐ pyrazolyl; 1,4‐Dihydropyridinyl‐pyrazolyl and 1,2,3,4‐tetrahydro pyrimidinyl‐pyrazolyl coumarins

Various 3‐[1‐phenyl‐4‐(2‐substituted‐5‐oxo‐oxazol‐4‐ylidenemethyl) pyrazol‐3‐yl] coumarins 4a‐f ; 3‐[1‐phenyl‐4‐(2,6‐dimethyl‐3,5‐disubstituted‐1,4‐dihydropyridin‐4‐yl) pyrazol‐3‐yl] coumarins 5a‐f and 3‐[1‐phenyl‐4‐(6‐methyl‐5‐substituted‐2‐oxo‐1,2,3,4‐tetrahydropyrimidin‐4‐yl) pyrazol‐3‐yl] coumarins 6a‐f have been synthesized utilizing Erlenmyer‐Plochl reaction, Hantzsch reaction and Biginelli reaction respectively using 3‐(1‐phenyl‐4‐formyl‐pyrazol‐3‐yl) coumarins 3a‐c as a starting material.