Divalent metal phosphonate coordination polymers constructed from a dipiperidine-based bisphosphonate ligand

The ligand 4,4'-dipiperidine-N,N'-bis(methylenephosphonic acid), H(4)L, has been reacted with divalent metal salts under solvothermal conditions to yield seven new metal phosphonate coordination polymers. The compounds have been characterized by elemental analyses and their structures determined by single-crystal X-ray diffraction. Zn(2)(L)(H(2)O)(2) and Co(2)(L)(H(2)O)(2) have (different) layered structures, while Mn(2)(L)(H(2)O)(3) has a chain motif. In these compounds, the N atoms of the ligand bind to the metal ions. α-Co(2)Cl(2)(H(2)L), formed from CoCl(2)·6H(2)O and H(4)L in ethanol, is also layered but the N atoms of the ligand are protonated. The Co atoms are tetrahedral, coordinated by three phosphonate oxygen atoms and a chloride ion. A polymorph of this compound, β-Co(2)Cl(2)(H(2)L), was obtained from a mixed ionic liquid under microwave irradiation. The primary difference between the polymorphs is the orientation of the phosphonate group relative to the dipiperidine. When reacted hydrothermally with Sn(II)C(2)O(4), H(4)L partially decomposes, producing phosphate ions which are incorporated into the structure of Sn(6)O(2)(H(2)L)(PO(4))(2)·4H(2)O. In this compound, the N atoms of the ligand are protonated, and two oxide anions are incorporated for charge balance. A second phase is obtained from the same reaction, which was determined to be Sn(7)O(L)(3). This compound has a layered structure which contains relatively large voids within the inorganic portion of the layer. These structures are discussed, as well as factors influencing the state of protonation in the final compounds. The choice of solvent and temperature were found to have a significant influence on the type of structure obtained.     

A new dimension in cyclic coinage metal pyrazolates: decoration with a second ring of coinage metals supported by inter-ring metallophilic interactions

When pyrazolate ligands with thioether chelate arms are used in cyclic coinage metal pyrazolates [Au(μ-pz)](n), the inner gold ring can be framed with an outer silver ring to give novel heterometallic double-crowned complexes [AuAg(μ-L(x))(BF(4))](4). They feature short intramolecular in-plane Ag-Au interactions, are stable as octanuclear species in solution, and show promising luminescence properties.     

Two-photon fluorescence microscopy imaging of cellular oxidative stress using profluorescent nitroxides

A range of varying chromophore nitroxide free radicals and their nonradical methoxyamine analogues were synthesized and their linear photophysical properties examined. The presence of the proximate free radical masks the chromophore's usual fluorescence emission, and these species are described as profluorescent. Two nitroxides incorporating anthracene and fluorescein chromophores (compounds 7 and 19, respectively) exhibited two-photon absorption (2PA) cross sections of approximately 400 G.M. when excited at wavelengths greater than 800 nm. Both of these profluorescent nitroxides demonstrated low cytotoxicity toward Chinese hamster ovary (CHO) cells. Imaging colocalization experiments with the commercially available CellROX Deep Red oxidative stress monitor demonstrated good cellular uptake of the nitroxide probes. Sensitivity of the nitroxide probes to H(2)O(2)-induced damage was also demonstrated by both one- and two-photon fluorescence microscopy. These profluorescent nitroxide probes are potentially powerful tools for imaging oxidative stress in biological systems, and they essentially "light up" in the presence of certain species generated from oxidative stress. The high ratio of the fluorescence quantum yield between the profluorescent nitroxide species and their nonradical adducts provides the sensitivity required for measuring a range of cellular redox environments. Furthermore, their reasonable 2PA cross sections provide for the option of using two-photon fluorescence microscopy, which circumvents commonly encountered disadvantages associated with one-photon imaging such as photobleaching and poor tissue penetration.     

A unified route to the welwitindolinone alkaloids: total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate, (-)-N-methylwelwitindolinone C isonitrile, and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate

As part of a comprehensive strategy to the welwitindolinone alkaloids possessing a bicyclo[4.3.1]decane core, we report herein concise asymmetric total syntheses of (-)-N-methylwelwitindolinone C isothiocyanate (2a), (-)-N-methylwelwitindolinone C isonitrile (2b), and (-)-3-hydroxy-N-methylwelwitindolinone C isothiocyanate (3a) from a common tetracyclic intermediate. The crucial vinyl chloride moiety was installed through electrophilic chlorination of a hydrazone, but only after adjustment of reactivity to circumvent a facile skeletal rearrangement. Selective desulfurization and oxidation of 2a provided access to 2b and 3a, respectively. Notably, this work provides corrected (1)H and (13)C NMR spectral data for 3a.     

Entropic and electrostatic effects on the folding free energy of a surface-attached biomolecule: an experimental and theoretical study

Surface-tethered biomolecules play key roles in many biological processes and biotechnologies. However, while the physical consequences of such surface attachment have seen significant theoretical study, to date this issue has seen relatively little experimental investigation. In response we present here a quantitative experimental and theoretical study of the extent to which attachment to a charged-but otherwise apparently inert-surface alters the folding free energy of a simple biomolecule. Specifically, we have measured the folding free energy of a DNA stem loop both in solution and when site-specifically attached to a negatively charged, hydroxylalkane-coated gold surface. We find that whereas surface attachment is destabilizing at low ionic strength, it becomes stabilizing at ionic strengths above ~130 mM. This behavior presumably reflects two competing mechanisms: excluded volume effects, which stabilize the folded conformation by reducing the entropy of the unfolded state, and electrostatics, which, at lower ionic strengths, destabilizes the more compact folded state via repulsion from the negatively charged surface. To test this hypothesis, we have employed existing theories of the electrostatics of surface-bound polyelectrolytes and the entropy of surface-bound polymers to model both effects. Despite lacking any fitted parameters, these theoretical models quantitatively fit our experimental results, suggesting that, for this system, current knowledge of both surface electrostatics and excluded volume effects is reasonably complete and accurate.     

Antibody-free reading of the histone code using a simple chemical sensor array

The histone code refers to the complex network of histone post-translational modifications that control gene expression and are of high interest as drivers of a large number of human diseases. We report here on a mix-and-match toolkit of readily available dyes and calixarene host molecules that can be combined to form dye-displacement sensors that respond to a wide variety of cationic peptides. Using the data from only two or three such simple supramolecular sensors as a chemical sensor array produces fingerprints of data that discriminate robustly among many kinds of histone code elements. "Reads" that are accomplished include the discrimination of unmethylated, mono-, di-, and trimethylated lysines on a single histone tail sequence, identification of different modifications and combinations of modifications on a single histone tail sequence, identification of a single modification type in several different sequence contexts, and identification of isomeric dimethylarginine modifications. Reads that are sometimes troublesome for antibodies are achieved. We also report on the ability of the sensor array to report simultaneously on the concentrations and identities of histone modifications. This sensor array discriminates between post-translationally modified analytes without being limited to partners that contain a single, programmed binding interaction.     

Rapid discovery of potent siRNA-containing lipid nanoparticles enabled by controlled microfluidic formulation

The discovery of potent new materials for in vivo delivery of nucleic acids depends upon successful formulation of the active molecules into a dosage form suitable for the physiological environment. Because of the inefficiencies of current formulation methods, materials are usually first evaluated for in vitro delivery efficacy as simple ionic complexes with the nucleic acids (lipoplexes). The predictive value of such assays, however, has never been systematically studied. Here, for the first time, by developing a microfluidic method that allowed the rapid preparation of high-quality siRNA-containing lipid nanoparticles (LNPs) for a large number of materials, we have shown that gene silencing assays employing lipoplexes result in a high rate of false negatives (~90%) that can largely be avoided through formulation. Seven novel materials with in vivo gene silencing potencies of >90% at a dose of 1.0 mg/kg in mice were discovered. This method will facilitate the discovery of next-generation reagents for LNP-mediated nucleic acid delivery.     

Colloidal synthesis of wurtzite Cu2ZnSnS4 nanorods and their perpendicular assembly

The quaternary copper chalcogenide Cu(2)ZnSnS(4) is an important emerging material for the development of low-cost and sustainable solar cells. Here we report a facile solution synthesis of stoichiometric Cu(2)ZnSnS(4) in size-controlled nanorod form (11 nm × 35 nm). The monodisperse nanorods have a band gap of 1.43 eV and can be assembled into perpendicularly aligned arrays by controlled evaporation from solution.     

Tuning the potentials of "extra" electrons in colloidal n-type ZnO nanocrystals via Mg2+ substitution

Colloidal reduced ZnO nanocrystals are potent reductants for one-electron or multielectron redox chemistry, with reduction potentials tunable via the quantum confinement effect. Other methods for tuning the redox potentials of these unusual reagents are desired. Here, we describe synthesis and characterization of a series of colloidal Zn(1-x)Mg(x)O and Zn(0.98-x)Mg(x)Mn(0.02)O nanocrystals in which Mg(2+) substitution is used to tune the nanocrystal reduction potential. The effect of Mg(2+) doping on the band-edge potentials of ZnO was investigated using electronic absorption, photoluminescence, and magnetic circular dichroism spectroscopies. Mg(2+) incorporation widens the ZnO gap by raising the conduction-band potential and lowering the valence-band potential at a ratio of 0.68:0.32. Mg(2+) substitution is far more effective than Zn(2+) removal in raising the conduction-band potential and allows better reductants to be prepared from Zn(1-x)Mg(x)O nanocrystals than can be achieved via quantum confinement of ZnO nanocrystals. The increased conduction-band potentials of Zn(1-x)Mg(x)O nanocrystals compared to ZnO nanocrystals are confirmed by demonstration of spontaneous electron transfer from n-type Zn(1-x)Mg(x)O nanocrystals to smaller (more strongly quantum confined) ZnO nanocrystals.     

Single molecule probes of membrane structure: orientation of BODIPY probes in DPPC as a function of probe structure

Single molecule fluorescence measurements have recently been used to probe the orientation of fluorescent lipid analogs doped into lipid films at trace levels. Using defocused polarized total internal reflection fluorescence microscopy (PTIRF-M), these studies have shown that fluorophore orientation responds to changes in membrane surface pressure and composition, providing a molecular level marker of membrane structure. Here we extend those studies by characterizing the single molecule orientations of six related BODIPY probes doped into monolayers of DPPC. Langmuir-Blodgett monolayers transferred at various surface pressures are used to compare the response from fluorescent lipid analogs in which the location of the BODIPY probe is varied along the length of the acyl chain. For each BODIPY probe location along the chain, comparisons are made between analogs containing phosphocholine and smaller fatty acid headgroups. Together these studies show a general propensity of the BODIPY analogs to insert into membranes with the BODIPY probe aligned along the acyl chains or looped back to interact with the headgroups. For all BODIPY probes studied, a bimodal orientation distribution is observed which is sensitive to surface pressure, with the population of BODIPY probes aligned along the acyl chains increasing with elevated surface pressure. Trends in the single molecule orientations for the six analogs reveal a configuration where optimal placement of the BODIPY probe within the acyl chain maximizes its sensitivity to the surrounding membrane structure. These results are discussed in terms of balancing the effects of headgroup association with acyl chain length in designing the optimal placement of the BODIPY probe.