Unlocking the binding and reaction mechanism of hydroxyurea substrates as biological nitric oxide donors

Hydroxyurea is the only FDA approved treatment of sickle cell disease. It is believed that the primary mechanism of action is associated with the pharmacological elevation of nitric oxide in the blood; however, the exact details of this are still unclear. In the current work, we investigate the atomic level details of this process using a combination of flexible-ligand/flexible-receptor virtual screening coupled with energetic analysis that decomposes interaction energies. Utilizing these methods, we were able to elucidate the previously unknown substrate binding modes of a series of hydroxyurea analogs to hemoglobin and the concomitant structural changes of the enzyme. We identify a backbone carbonyl that forms a hydrogen bond with bound substrates. Our results are consistent with kinetic and electron paramagnetic resonance (EPR) measurements of hydroxyurea-hemoglobin reactions, and a full mechanism is proposed that offers new insights into possibly improving substrate binding and/or reactivity.     

Synthesis of 1,2,3-triazole-fused heterocycles via Pd-catalyzed cyclization of 5-iodotriazoles

A convenient approach toward polycyclic frameworks containing fused 1,2,3-triazoles is described. The synthesis consists of a Cu-catalyzed cycloaddition and an intramolecular Pd-catalyzed direct arylation or Heck reaction, and affords the products in good to excellent yields.     

基于近红外光谱的人参与西洋参的快速鉴别研究

基于近红外光谱分析技术结合模式判别方法建立了一种人参和西洋参鉴别的新方法。收集根状、根须和粉末状的样品共90份,在有聚乙烯包装袋的情况下直接采集近红外光谱,去除原始光谱中包装袋的显著吸收后进行了MSC与一阶导数处理,然后采用移动窗口偏最小二乘法选择了建模光谱区间,分别建立了PLS-DA,PCA-DA和SVM判别模型,并对3种模型作了对比分析,结果表明SVM判别效果最优,其对预测集的正确判别率为100%。该方法准确、便捷,可实际应用于企业原料药材的质量控制,实现对原料药材的快速筛查。     

Mixed-metal sandwich complexes [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14- (M(II) = Co, Mn): synthesis and stability. The molecular structure of [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14-

Two new mixed-metal sandwich complexes [M(II)2(H2O)2Fe(III)2(P2W15O56)2]14- (abbreviated [M2Fe2P4W30], M(II) = Co(II), Mn(II)) were obtained at pH 3 by addition of M2+ to [Na2(H2O)2Fe(III)2(P2W15O56)2]16- (abbreviated [Na2Fe2P4W30]) without substitution in the alpha-[P2W15O56]12- (abbreviated [P2W15]) units. Their X-ray structures are reported. At lower pH, back conversion to [Na2Fe2P4W30] was followed by 31P NMR, electrochemistry and UV-visible spectroscopy. The preparation and the characterization in solution of the lacunary intermediate [NaCo(II)(H2O)2Fe(III)2(P2W15O56)2]15- (abbreviated [NaCoFe2P4W30]) is also described.     

Comparative analysis by gas chromatography-mass spectrometry of the essential oils from bark and leaves of Cedrelopsis grevei Baill, an aromatic and medicinal plant from Madagascar

The essential oils from bark and leaves of Cedrelopsis grevei Baill (Ptaeroxylaceae), an aromatic and medicinal plant from Madagascar, are widely used in folk medicine. These two commercially available oils have been examined separately by means of GC-MS. The oil constituents were identified according to their mass spectra and their relative retention indices determined on both polar and non-polar stationary phase capillary columns. A total of 55 compounds have been identified constituting 76.7% (bark) and 91.6% (leaves) of the volatile constituents. Both oils were found to have a similar composition; however the relative percentages of some compounds notably differed. The bark essential oil contained beta-pinene (17.1%), cis-sesquisabinene hydrate (12.8%) and caryophyllene oxide (7.0%) as the main components whereas the leaf essential oil was largely dominated by trans-beta-farnesene (35.6%); beta-pinene (12.8%), cis-sesquisabinene hydrate (9.8%) and ar-curcumene (8.6%) were also present as major components. As far as we know, this is the first report on the Cedrelopsis grevei bark and leaf essential oils which therapeutic properties may be attractive for aromatherapy.     

Stereoselective synthesis of acortatarins a and B

Acortatarins A and B have been synthesized via stereoselective spirocyclizations of glycals. Mercury-mediated spirocyclization of a pyrrole monoalcohol side chain leads to acortatarin A. Glycal epoxidation and reductive spirocyclization of a pyrrole dialdehyde side chain leads to acortatarin B. Acid equilibration and crystallographic analysis indicate that acortatarin B is a contrathermodynamic spiroketal with distinct ring conformations compared to acortatarin A.     

Spectroscopic and Electrochemical Study of the Interconversion and Decomplexation of Cobalt(II) Sandwich Polyoxometalates Based on a Dawson-Type Anion

The reaction of the trivacant Dawson polyoxometalate α-[P(2)W(15)O(56)](12-) and the divalent cations Co(2+) is known to form a symmetrically derived sandwich complex of formula ββ-[Co(4)(H(2)O)(2)(P(2)W(15)O(56))(2)](16-) [symbolized as ββ-Co(4)(P(2)W(15))(2)] at low pH (ca. pH 3). We have shown previously that, by a slight modification of the reaction conditions, trinuclear αβ-[(NaOH(2))Co(3)(H(2)O)(P(2)W(15)O(56))(2)](17-) and dinuclear [(NaOH(2))(2)Co(2)(P(2)W(15)O(56))(2)](18-) complexes [symbolized as αβ-NaCo(3)(P(2)W(15))(2) and Na(2)Co(2)(P(2)W(15))(2), respectively] can be synthesized as aqueous-soluble sodium salts. αβ-NaCo(3)(P(2)W(15))(2) is a "lacunary" sandwich complex that can add a Co(2+) cation to form nearly quantitatively an unsymmetrical Dawson tetracobalt sandwich polyoxometalate, αβ-[Co(4)(H(2)O)(2)(P(2)W(15)O(56))(2)](16-) [symbolized as αβ-Co(4)(P(2)W(15))(2)]. Thus, for Co(4)(P(2)W(15))(2), the junctions between the trivacant {P(2)W(15)} subunits and the central tetrameric unit can be either both β type or β and α types. The interconversion between αβ-Co(4)(P(2)W(15))(2) and ββ-Co(4)(P(2)W(15))(2) and the decomplexation process at low pH, leading to the formation of αβ-NaCo(3)(P(2)W(15))(2) and/or Na(2)Co(2)(P(2)W(15))(2), have been followed in aqueous solution at various pH values by electrochemistry, UV-visible absorption spectroscopy, and (31)P NMR spectroscopy.     

Thermal degradation of poly(methyl-n-hexylsilylene)

Thermal degradation of poly(methyl-n-hexylsilane) in the solid state in absence of oxygen reveals formation of a cyclic pentamer between 150 and 250°C. Polymer is gradually degraded to an intermediate molecular weight distribution. The weight average of this new distribution is not only temperature-dependent, but is also a function of viscosity of the polymer and nature of chain ends. As no insolubles or Si? H groups are formed, the degradation mechanism is most likely a back-biting mechanism induced by active chain ends such as silyl anions or Si? Cl rather than a homolytic cleavage of the main chain. A concurrent intramolecular rearrangement reaction is also proposed. Moreover, this study proposes an explanation to the trimodal molecular weight distribution obtained by the Wurtz coupling of dichlorosilanes with molten sodium in refluxing toluene. © 1995 John Wiley & Sons, Inc.     

Electron transfer rates in DNA films as a function of tether length

A homologous series of DNA-modified electrodes has been investigated in which the molecular tether length varies. Using intercalated, covalently bound daunomycin as a redox probe, an exponential dependence of electron transfer rates on the number of intervening methylene groups in the sigma-bonded tether is observed. In contrast, variation in DM position within DNA yields no detectable change in rate. These data confirm that overall electron transfer rates in DNA films are limited by the tether, not the DNA.     

Polypropylene ionic thermoplastic elastomers: Synthesis and properties

Polypropylene ionic thermoplastic elastomers have been prepared by melt radical grafting of maleic anhydride onto polypropylene in the presence of N-bromosuccinimide followed by neutralization of the resulting elastomeric grafted polypropylene using sodium salts. Sodium hydroxide and sodium acetate were compared in aqueous solution, as anhydrous or hydrated powders. The neutralization reaction was followed by Fourier transform infrared spectroscopy, allowing the development of a method to determine the effective neutralization degree. Important physical changes were recorded upon neutralization. Especially thermal stability, shear storage modulus and complex viscosity in the flow region were largely increased as a function of the neutralization degree.