Direct observation of phenylalanine orientations in statherin bound to hydroxyapatite surfaces

Extracellular biomineralization proteins such as salivary statherin control the growth of hydroxyapatite (HAP), the principal component of teeth and bones. Despite the important role that statherin plays in the regulation of hard tissue formation in humans, the surface recognition mechanisms involved are poorly understood. The protein-surface interaction likely involves very specific contacts between the surface atoms and the key protein side chains. This study demonstrates for the first time the power of combining near-edge X-ray absorption fine structure (NEXAFS) spectroscopy with element labeling to quantify the orientation of individual side chains. In this work, the 15 amino acid N-terminal binding domain of statherin has been adsorbed onto HAP surfaces, and the orientations of phenylalanine rings F7 and F14 have been determined using NEXAFS analysis and fluorine labels at individual phenylalanine sites. The NEXAFS-derived phenylalanine tilt angles have been verified with sum frequency generation spectroscopy.     

Synthesis and nonlinear optical properties of fluorine-containing naphthalocyanines

The fluorine-containing metal naphthalocyanines [F16NcGaCl] (7) and [(F16NcGa)2O] (8), which represent the first examples of peripherally fluorine substituted naphthalocyanines, were synthesized, and the nonlinear optical transmission was studied. Peripheral substitution by fluorine atoms enhances the solubility and photostability of the naphthalocyanines. In particular, for the axially mu-oxo-bridged naphthalocyanine dimer 8, practically no aggregation was observed in organic solvents and it has proved to be an efficient optical limiter when irradiated with laser light pulses at the wavelength of 532 nm, with pulse duration of 5 ns and repetition rate of 20 Hz.     

How Good is Fluorine as a Hydrogen‐Bond Acceptor in Fluorinated Single‐Walled Carbon Nanotubes?

Ab initio (RI-MP2/TZVPP) computations were employed to investigate the interaction between hydrogen-bond donors H2O and CH3OH and covalently bound fluorine in organofluorine compounds. While the CFHO interaction energy is around 3 kcal mol(-1) for unstrained systems, the linear correlation between pyramidalization angle at the carbon atom and the interaction energy suggests that increased binding can be obtained in strained systems. This is confirmed for the dihydrodifluoropyrene-methanol pair, but a large portion of the binding energy is due to the interaction of the pi system with the oxygen atom. Density functional periodic boundary condition computations (PBC-PBE/6-31G*) of the structures of (5,5) and (10,10) armchair (C2F)n fluorinated SWNTs (F-SWNTs) indicate that the pyramidalization at the fluorine-binding carbon atoms are too similar to that of CH3F to enhance the hydrogen-bond acceptor properties of fluorine significantly. The solubility of F-SWNTs in alcohols therefore could be due to a combination of hydrogen bonds and van der Waals interactions with the pi systems.     

Synthesis of gemini surfactants with twelve symmetric fluorine atoms and one singlet F MR signal as novel F MRI agents

A family of fluorinated gemini surfactants derived from perfluoropinacol has been synthesized as novel ¹⁹F magnetic resonance imaging (¹⁹F MRI) agents. These fluorinated surfactants with 12 symmetric fluorine atoms and one singlet ¹⁹F MR peak can be conveniently prepared from perfluoropinacol and oligo(ethylene glycols) on multi-gram scales. Solubility, hydrophilicity (log P), and critical micelle concentration (CMC) measurements of these fluorinated surfactants indicated that high aqueous solubility can be achieved by introducing oligo(ethylene glycols) with appropriate length into perfluoropinacol, i.e., manipulating the fluorine content (F%). One of these fluorinated surfactants with high aqueous solubility and excellent ¹⁹F MR properties has been identified by ¹⁹F MRI phantom experiments as a promising ¹⁹F MRI agent.     

Effects of fluorine on the structures and energetics of the propynyl and propargyl radicals and their anions

[reaction: see text] The adiabatic electron affinity (EA(ad)) of the CH(3)-C[triple bond]C(*) radical [experiment = 2.718 +/- 0.008 eV] and the gas-phase basicity of the CH(3)-C[triple bond]C:(-) anion [experiment = 373.4 +/- 2 kcal/mol] have been compared with those of their fluorine derivatives. The latter are studied using theoretical methods. It is found that there are large effects on the electron affinities and gas-phase basicities as the H atoms of the alpha-CH(3) group in the propynyl system are substituted by F atoms. The predicted electron affinities are 3.31 eV (FCH(2)-C[triple bond]C(*)), 3.86 eV (F(2)CH-C[triple bond]C(*)), and 4.24 eV (F(3)C-C[triple bond]C(*)), and the predicted gas-phase basicities of the fluorocarbanion derivatives are 366.4 kcal/mol (FCH(2)-C[triple bond]C:(-)), 356.6 kcal/mol (F(2)CH-C[triple bond]C:(-)), and 349.8 kcal/mol (F(3)C-C[triple bond]C:(-)). It is concluded that the electron affinities of fluoropropynyl radicals increase and the gas-phase basicities decrease as F atoms sequentially replace H atoms of the alpha-CH(3) in the propynyl system. The propargyl radicals, lower in energy than the isomeric propynyl radicals, are also examined and their electron affinities are predicted to be 0.98 eV ((*)CH(2)-C[triple bond]CH), 1.18 eV ((*)CFH-C[triple bond]CH), 1.32 eV ((*)CF(2)-C[triple bond] CH), 1.71 eV ((*)CH(2)-C[triple bond]CF), 2.05 eV ((*)CFH-C[triple bond]CF), and 2.23 eV ((*)CF(2)-C[triple bond]CF).     

Quantum chemical study of IrFn (n = 1–7) clusters: An investigation of superhalogen properties

In present investigation, the interactions of iridium (Ir) atom with fluorine (F) atoms have been studied using the density functional theory. Up to seven F atoms were able to bind to a single Ir atom which resulted in increase of electron affinities successively, reaching a peak value of 7.85 eV for IrF₇. The stability and reactivity of these clusters were analyzed by calculating highest occupied molecular orbital (HOMO)–LUMO gaps, molecular orbitals and binding energies of these clusters. The unusual properties of these clusters are due to the involvement of inner shell 5d‐electrons, which not only allows IrF_n clusters to belong to the class of superhalogens but also shows that its valence can exceed the nominal value of 2. © 2012 Wiley Periodicals, Inc.     

A phosphotyrosine-imprinted polymer receptor for the recognition of tyrosine phosphorylated peptides

Hyperphosphorylation at tyrosine is commonly observed in tumor proteomes and, hence, specific phosphoproteins or phosphopeptides could serve as markers useful for cancer diagnostics and therapeutics. The analysis of such targets is, however, a challenging task, because of their commonly low abundance and the lack of robust and effective preconcentration techniques. As a robust alternative to the commonly used immunoaffinity techniques that rely on phosphotyrosine(pTyr)-specific antibodies, we have developed an epitope-imprinting strategy that leads to a synthetic pTyr-selective imprinted polymer receptor. The binding site incorporates two monourea ligands placed by preorganization around a pTyr dianion template. The tight binding site displayed good binding affinities for the pTyr template, in the range of that observed for corresponding antibodies, and a clear preference for pTyr over phosphoserine (pSer). In further analogy to the antibodies, the imprinted polymer was capable of capturing short tyrosine phosphorylated peptides in the presence of an excess of their non-phosphorylated counterparts or peptides phosphorylated at serine.     

Theoretical investigation of in-plane hydrogen-bonded complexes of ammonia with partially substituted fluorobenzenes

Systematic investigation of in-plane hydrogen-bonded complexes of ammonia with partially substituted fluorobenzenes has revealed that fluorobenzene, difluorobenzene, and trifluorobenzene favor formation of cyclic complexes with a C-H...N-H...F-C binding motif. On the other hand, tetrafluorobenzene and pentafluorobenzene favor formation of linear C-H...N hydrogen-bonded complexes. The complete absence of exclusively linear N-H...F hydrogen-bonded complexes for the entire series indicates that C-F bond in fluorobenzenes is a reluctant hydrogen-bond acceptor. However, fluorine does hydrogen bond when cooperatively stabilized with C-H...N hydrogen bonds for the lower fluoro analogues. The propensity of fluorobenzenes to adapt to the C-H...N-H...F-C binding motif decreases with the progressive fluorination of the benzene ring and disappears completely when benzene ring is substituted with five or more fluorine atoms.     

Stabilization of zwitterions in solution: phosphinic and phosphonic acid GABA analogues

The influence of treatment of electron correlation, size of basis set and choice of solvation model on the predicted stabilization of zwitterionic phosphinic and phosphonic acid gamma-aminobutyric acid (GABA) analogues is investigated using ab initio molecular orbital methods and density functional theory. Density functional theory with the B3LYP functional and a composite basis set composed of the 6-31+G(2df) basis for phosphorus atoms and the 6-31+G(d,p) basis set for all other atoms is found to give an acceptable tradeoff between accuracy and computational expense. Either directly optimizing zwitterionic conformers within the conductor-like screening solvation model (COSMO) or pre-optimizing as dihydrates and then applying the COSMO solvation model give an acceptable treatment of solvation in terms of determining stable solvated structures, although directly optimizing within COSMO is simpler and less computationally expensive. With this protocol, cis-constrained phosphinic and phosphonic acid GABA analogues, which exhibit lower affinities for GABAC receptors, are found to possess only folded, intramolecularly hydrogen bonded low energy conformers. Trans-constrained analogues, on the other hand, exhibit higher affinities for GABAC receptors and are found to exist only as partially folded stable conformers. Conformationally flexible analogues can attain folded, partially folded or fully extended conformations and also have high biological activity. These results imply that the partially folded conformation is likely to be the most biologically active.     

First principle study of CrF n (n = 1–7) nano clusters: An investigation of superhalogen properties

Quantum chemical calculations using gradient corrected density functional theory at B3LYP level reveals the unusual properties of a chromium (Cr) atom interacting with fluorine (F) atoms. Up to seven F atoms are bound to a single Cr atom, which results in increase of electron affinities as successive fluorine atoms are attached, reaching a peak value of 7.14 eV for CrF₆. The large HOMO–LUMO energy gap, both in neutral and anionic form, further provide evidence of their stability. These unusual properties brought about by involvement of inner shell 3d-electrons, which not only allow CrF _n (n = 1–7) clusters to belong to the class of superhalogens but also show that its valence can exceed the nominal value of 2.     

Fluorine-NMR experiments for high-throughput screening: theoretical aspects,practical considerations,and range of applicability

Competition ligand-based NMR screening experiments have recently been introduced to overcome most of the problems associated with traditional ligand-based NMR screening. Molecules with marginal solubility and high affinity for a given target can be easily identified in a high-throughput manner by screening chemical mixtures against the target in the presence of a weak- to medium-affinity ligand of known binding constant. While the original competition-based approaches utilized (1)H detection, significant advantages are obtained using (19)F detection. The absence of spectral overlap permits the screening of large chemical mixtures and allows for automated analysis of the spectra, even in the presence of protonated buffers, solvents, and detergents. The large chemical shift anisotropy of fluorine and the significant exchange contribution allow for the selection of a weak-affinity spy molecule, thus resulting in a lower binding affinity threshold for the identified NMR hits. The method, labeled FAXS (fluorine chemical shift anisotropy and exchange for screening) is rapid and requires only a limited amount of protein and, therefore, compares favorably with the other established non-NMR techniques used in high-throughput screening. Herein the theoretical aspects of this powerful (19)F-based approach are presented and discussed in detail. The experimental conditions together with the detection limits and binding constant measurements are investigated using human serum albumin as the target.     

Stereoselective Synthesis of Fluorinated Galactopyranosides as Potential Molecular Probes for Galactophilic Proteins: Assessment of Monofluorogalactoside–LecA Interactions

The replacement of hydroxyl groups by fluorine atoms on hexopyranoside scaffolds may allow access to invaluable tools for studying various biochemical processes. As part of ongoing activities toward the preparation of fluorinated carbohydrates, a systematic investigation involving the synthesis and biological evaluation of a series of mono- and polyfluorinated galactopyranosides is described. Various monofluorogalactopyranosides, a trifluorinated, and a tetrafluorinated galactopyranoside have been prepared using a Chiron approach. Given the scarcity of these compounds in the literature, in addition to their synthesis, their biological profiles were evaluated. Firstly, the fluorinated compounds were investigated as antiproliferative agents using normal human and mouse cells in comparison with cancerous cells. Most of the fluorinated compounds showed no antiproliferative activity. Secondly, these carbohydrate probes were used as potential inhibitors of galactophilic lectins. The first transverse relaxation-optimized spectroscopy (TROSY) NMR experiments were performed on these interactions, examining chemical shift perturbations of the backbone resonances of LecA, a virulence factor from Pseudomonas aeruginosa. Moreover, taking advantage of the fluorine atom, the ¹⁹F NMR resonances of the monofluorogalactopyranosides were directly monitored in the presence and absence of LecA to assess ligand binding. Lastly, these results were corroborated with the binding potencies of the monofluorinated galactopyranoside derivatives by isothermal titration calorimetry experiments. Analogues with fluorine atoms at C-3 and C-4 showed weaker affinities with LecA as compared to those with the fluorine atom at C-2 or C-6. This research has focused on the chemical synthesis of “drug-like” low-molecular-weight inhibitors that circumvent drawbacks typically associated with natural oligosaccharides.     

Single crystal structure determination of a new zirconium N-ethylpyridinium phosphonate: Zr(O(3)PCH(2)CH(2)NC(5)H(5))(F(-))(3)

We describe the structure of a new zirconium N-ethylpyridinium phosphonate, Zr(O(3)PCH(2)CH(2)NC(5)H(5))(F(-))(3), that has been determined by single-crystal X-ray analysis (monoclinic, P2(1)/c (No. 14), a = 12.3634(12) A, b = 9.3090(17) A, c = 9.8077(13) A, beta = 112.819(8) degrees, V = 1040.4(3) A(3), Z = 4). This structure is unlike any other reported zirconium phosphonate. Octahedral coordination about zirconium is completed by three oxygen atoms of three different phosphonate groups and three fluoride ligands. The structure is composed of corrugated infinite layers of these Zr octahedra that corner share their three oxygen atoms with the phosphonate tetrahedra. The appended cationic pyridinium groups lie between the inorganic sheets and are charge-balanced by the [Zr(O(3)P-)(3)F(3)](-) octahedra. This structure represents a new example of the structure-directing influence of cationic organic ligands on the zirconium phosphonate framework.     

Utilization of 3'-carboxy-containing tyrosine derivatives as a new class of phosphotyrosyl mimetics in the preparation of novel non-phosphorylated cyclic peptide inhibitors of the Grb2-SH2 domain

A new class of phosphotyrosyl (pTyr) mimetics, distinct from the conventional pTyr mimetic design of adding non-hydrolyzable acidic functionalities to the 4'-position of phenylalanine, was created by introducing carboxy-containing groups to the 3'-position of tyrosine. The effect of the chain length of the carboxy substituent was examined. Reported herein is the chiral pool synthesis of the new pTyr mimetics, and their first use in a novel non-phosphorylated Grb2-SH2 domain binding motif with the 5-amino-acid sequence Xx1-Leu-(3'-substituted-Tyr)-Ac6c-Asn. The highest affinity was exhibited by the 3-L-(2-carboxyethyl)tyrosine-containing sulfoxide-cyclized peptide , with an IC50 = 1.1 microM, providing a promising new template for further development of potent Grb2-SH2 domain inhibitors with reduced charge and peptidic nature, but improved selectivity and bioavailability.     

X-ray photoelectron spectroscopy as detection tool for coordinated or uncoordinated fluorine atoms demonstrated on fluoride systems NaF,K2TaF7, K3TaF8, K2ZrF6, Na7Zr6F31 and K3ZrF7

While systems K₃TaF₈ and K₃ZrF₇ were prepared by modified molten salt method modified wet pathway was used for reproducible preparation of Na₇Zr₆F₃₁. Its congruently melting character was demonstrated on simultaneous TG/DSC measurements and XRD patterns. X-ray photoelectron spectroscopy was applied for identification of differently bonded fluorine atoms in series of compounds NaF, K₂TaF₇, K₃TaF₈, K₂ZrF₆, Na₇Zr₆F₃₁ and K₃ZrF₇. Three different types of fluorine atoms were described qualitatively and quantitatively. Uncoordinated fluorine atoms (F⁻) provide signals at lowest binding energies, followed by signals from terminally coordinated fluorine atoms (M–F) and then bridging fluorine atoms (M–F–M) at highest energy. Based on XPS F 1s signals assigned to fluorine atoms in compounds with correctly determined structure it was suggested that fluorine atoms in K₃ZrF₇ have partially bridging character.     

Ion size influence on the Ar solvation shells of M(+)-C6F6 clusters (M = Na, K, Rb, Cs)

The size-specific influence of alkali metal ions in the gradual transition from cluster rearrangement to solvation dynamics is investigated by means of molecular dynamics simulations for alkali metal cation-hexafluorobenzene systems, M(+)-C(6)F(6) (M = Na, K, Rb and Cs), surrounded by Ar atoms. To analyze such transition, different small aggregates of the M(+)-C(6)F(6)-Ar(n) (n = 1, ..., 30) type and M(+)-C(6)F(6) clusters solvated by about 500 Ar atoms are considered. The Ar-C(6)F(6) interaction contribution has been described using two different formalisms, based on the interaction decomposition in atom-bond and in atom-effective atom terms, which have been applied to study the small aggregates and to investigate the Ar solvated M(+)-C(6)F(6) clusters, respectively. The selectivity of the promoted phenomena from the M(+) ion size and their dependence from the number of Ar atoms is characterized.     

Enantioselective synthesis of protected L-4-[sulfonamido(difluoromethyl)]phenylalanine and L-4-[sulfonamido(methyl)]phenylalanine and an examination of hexa- and tripeptide platforms for evaluating pTyr mimics for PTP1B inhibition

The first enantioselective syntheses of L-4-(sulfonamidomethyl)phenylalanine and L-[sulfonamido(difluoromethyl)]phenylalanine suitably protected for peptide syntheses are described. A key step in the synthesis of L-(sulfonamidomethyl)phenylalanine was an oxidative chlorination on Ac-L-Phe(4-CH2SCOCH3)-OEt to give crude Ac-L-Phe(4-CH2SO2Cl)-OEt, which could be reacted with amines to give the corresponding sulfonamides. Key to the preparation of L-[sulfonamido(difluoromethyl)]phenylalanine was a highly enantioselective reaction involving William's auxiliary and a benzylic bromide intermediate. These amino acids were incorporated into two peptide sequences, DADE-X-LNH2 and FmocGlu(OBn)-X-LNH2, which have previously been employed as platforms for assessing pTyr mimics for inhibition of protein tyrosine phosphatase 1B (PTP1B). Inhibition studies with these and other peptides and PTP1B revealed that good inhibition could be obtained using the tripeptide platform, although the presence of a pTyr mimic was not required for good inhibition. These results suggest that the FmocGlu(OBn)-X-LNH2 tripeptide platform is not suitable for assessing pTyr mimics for PTP1B inhibition.     

The Osmium(VIII) Oxofluoro Cations OsO(2)F(3)(+) and F(cis-OsO(2)F(3))(2)(+): Syntheses, Characterization by (19)F NMR Spectroscopy and Raman Spectroscopy, X-ray Crystal Structure of F(cis-OsO(2)F(3))(2)(+)Sb(2)F(11)(-), and Density Functional Theory Calculations of OsO(2)F(3)(+), ReO(2)F(3), and F(cis-OsO(2)F(3))(2)(+)

Osmium dioxide tetrafluoride, cis-OsO(2)F(4), reacts with the strong fluoride ion acceptors AsF(5) and SbF(5) in anhydrous HF and SbF(5) solutions to form orange salts. Raman spectra are consistent with the formation of the fluorine-bridged diosmium cation F(cis-OsO(2)F(3))(2)(+), as the AsF(6)(-) and Sb(2)F(11)(-) salts, respectively. The (19)F NMR spectra of the salts in HF solution are exchange-averaged singlets occurring at higher frequency than those of the fluorine environments of cis-OsO(2)F(4). The F(cis-OsO(2)F(3))(2)(+)Sb(2)F(11)(-) salt crystallizes in the orthorhombic space group Imma. At -107 degrees C, a = 12.838(3) ?, b = 10.667(2) ?, c = 11.323(2) ?, V = 1550.7(8) ?(3), and Z = 4. Refinement converged with R = 0.0469 [R(w) = 0.0500]. The crystal structure consists of discrete fluorine-bridged F(cis-OsO(2)F(3))(2)(+) and Sb(2)F(11)(-) ions in which the fluorine bridge of the F(cis-OsO(2)F(3))(2)(+) cation is trans to an oxygen atom (Os-O 1.676 ?) of each OsO(2)F(3) group. The angle at the bridge is 155.2(8) degrees with a bridging Os---F(b) distance of 2.086(3) ?. Two terminal fluorine atoms (Os-F 1.821 ?) are cis to the two oxygen atoms (Os-O 1.750 ?), and two terminal fluorine atoms of the OsO(2)F(3) group are trans to one another (1.813 ?). The OsO(2)F(3)(+) cation was characterized by (19)F NMR and by Raman spectroscopy in neat SbF(5) solution but was not isolable in the solid state. The NMR and Raman spectroscopic findings are consistent with a trigonal bipyramidal cation in which the oxygen atoms and a fluorine atom occupy the equatorial plane and two fluorine atoms are in axial positions. Density functional theory calculations show that the crystallographic structure of F(cis-OsO(2)F(3))(2)(+) is the energy-minimized structure and the energy-minimized structures of the OsO(2)F(3)(+) cation and ReO(2)F(3) are trigonal bipyramidal having C(2)(v)() point symmetry. Attempts to prepare the OsOF(5)(+) cation by oxidative fluorination of cis-OsO(2)F(4) with KrF(+)AsF(6)(-) in anhydrous HF proved unsuccessful.     

Molecular dynamics simulations of trans-1,4,5,8-tetranitro-1,4,5,8-tetraazadecalin-based polymer-bonded explosives

Molecular dynamics has been applied to investigate the low-sensitivity explosive TNAD (trans-1,4,5,8-tetranitro-1,4,5,8-tetraazadecalin)-based polymer-bonded explosives (PBXs) with four typical fluorine polymers, PVDF (polyvinylidenedifluoride), PCTFE (polychlorotrifluoroethylene), F(2311) (fluorine rubber), and F(2314) (fluorine resin). The elastic constants, mechanical properties (tensile modulus, bulk modulus, shear modulus, and Poission ratio), binding energies, and detonation performances are first reported for the TNAD-based PBXs. The results show that the mechanical properties of TNAD can be effectively improved by the addition of small amounts of fluorine polymers, and the overall effect of fluorine polymers on the mechanical properties of the PBXs along three crystalline surfaces is (001) > (010) > (100). On each crystal surface, improvement in the ductibility made by the fluorine polymers changes approximately in the sequence of PVDF > F(2311) > F(2314) > PCTFE. The binding energies between different TNAD crystalline surfaces and different polymer binders with the same chain segment or mass fraction both decrease in the order of (010) > (100) > (001). The binding properties of the polymers with the same chain segment on each crystal surface of TNAD increase as PVDF < F(2311) < F(2314) < PCTFE, while those of different polymers in the same content decrease in the sequence of PVDF > F(2311) > F(2314) > PCTFE. The detonation performances of the PBXs decrease in comparison with the pure crystal, but they are superior to those of TNT.     

新型二氟甲基磷酸类酪氨酸蛋白磷酸酯酶1B抑制剂的分子动力学模拟和结合自由能计算

通过分子对接建立了一系列含二氟甲基磷酸基团(DFMP)或二氟甲基硫酸基团(DFMS)的抑制剂与酪氨酸蛋白磷酸酯酶1B(PTP1B)的相互作用模式, 并通过1 ns的分子动力学模拟和molecular mechanics/generalized Born surface area (MM/GBSA)方法计算了其结合自由能. 计算获得的结合自由能排序和抑制剂与靶酶间结合能力排序一致; 通过基于主方程的自由能计算方法, 获得了抑制剂与靶酶残基间相互作用的信息, 这些信息显示DFMP/DFMS基团的负电荷中心与PTP1B的221位精氨酸正电荷中心之间的静电相互作用强弱决定了此类抑制剂的活性, 进一步的分析还显示位于DFMP/DFMS基团中的氟原子或其他具有适当原子半径的氢键供体原子会增进此类抑制剂与PTP1B活性位点的结合能力.