3-Oxodapagliflozin as a Potent and Highly Selective SGLT2 Inhibitor for the Treatment of Type 2 Diabetes

Structural modifications of 3-OH in the glucose moiety of dapagliflozin（1）, an approved potent sodium-dependent glucose transporter 2（SGLT2） inhibitor, led to 3-oxodapagliflozin（16）, a highly potent and more selective SGLT2 inhibitor[IC50（hSGLT1）/IC50（hSGLT2）=2851 for compound 16 vs. 843 for compound 1]. 3-Oxodapagliflozin（16） exhibited in vitro（IC50=1.0nmol/L against hSGLT2 for compound 16 vs. 1.3 nmol/L for compound 1） and in vivo activities comparable to those of dapagliflozin（1）. The bioactivities of 3-oxodapagliflozin （16） warrant its further evaluation as a promising SGLT2 inhibitor for the treatment of type 2 diabetes.     

CoMFA and CoMSIA studies on C-aryl glucoside SGLT2 inhibitors as potential anti-diabetic agents

SGLT2 has become a target of therapeutic interest in diabetes research. CoMFA and CoMSIA studies were performed on C-aryl glucoside SGLT2 inhibitors (180 analogues) as potential anti-diabetic agents. Three different alignment strategies were used for the compounds. The best CoMFA and CoMSIA models were obtained by means of Distill rigid body alignment of training and test sets, and found statistically significant with cross-validated coefficients (q ²) of 0.602 and 0.618, respectively, and conventional coefficients (r ²) of 0.905 and 0.902, respectively. Both models were validated by a test set of 36 compounds giving satisfactory predicted correlation coefficients (r ² _pred) of 0.622 and 0.584 for CoMFA and CoMSIA models, respectively. A comparison was made with earlier 3D QSAR study on SGLT2 inhibitors, which shows that our 3D QSAR models are better than earlier models to predict good inhibitory activity. CoMFA and CoMSIA models generated in this work can provide useful information to design new compounds and helped in prediction of activity prior to synthesis.     

Design, synthesis and biological activity of cyclohexane-bearing C-glucoside derivatives as SGLT2 inhibitors

Seven cyclohexane-bearing C-glucoside derivatives (7, 9, 12, 13 and 17-19) were designed and synthesized as SGLT2 inhibitors starting from a potent SGLT2 inhibitor we discovered in earlier work, (1S)-1-deoxy-1-[4-methoxy-3-(trans-n-propylcyclohexyl)methylphenyl]-D-glucose (1). The in vitro and in vivo biological activities were evaluated by hSGLT2/hSGLT1 inhibition and urinary glucose excretion (UGE), respectively. Among the synthesized compounds 12, the 6-deoxy derivative of 1 was the most active and selective SGLT2 inhibitor (IC50 = 1.4 nmol/L against hSGLT2; selectivity = 1576). Compound 12 was a potent SGLT2 inhibitor, which could induce more urinary glucose than 1 and dapagliflozin in UGE.     

Investigation of the Interaction between Isoflavonoids and Bovine Serum Albumin by Fluorescence Spectroscopy

The interactions of bovine serum albumin （BSA） with three structurally related isoflavonoids, genistein, puerarin and daidzein, were studied under physiological conditions by fluorescence spectroscopic technique. The quenching mechanism of these compounds with BSA was suggested as static quenching and the binding constants were determined at different temperatures based on the fluorescence quenching results. The transfer efficiency of energy and distance between the acceptor and BSA were investigated on the basis of the mechanism of the Forster energy transference. According to the thermodynamic parameters it has been suggested that the acting force be mainly hydrophobic force. The comparison of binding potency of the three isoflavonoids to BSA showed that the substitution by 5-OH and 8-Glc could enhance the binding affinity. All these obtained in the work can make us better understand the mode of the action and pharmacological activities of the isoflavonoids.     

Facile Synthesis and Crystal Structures of New Ammonium Sulfonates （CA-DNBS and TEA-TMBS）

The title compounds, C12HIoN307SCI （I） and C15H27NO3S （II）, crystallize in the monoclinic system, space group P21/c with a = 7.3995（1）, b = 27.8489（6）, c = 9.8246（2）/, fl = 131.349（1）, V = 1519.82（5） A3, Z = 4, F（000） = 768, Rint = 0.033 and S = 1.03 for I, and in the orthorhombic system, space group Pbca with a = 8.6227（1）, b = 16.1480（4）, c = 23.8774（6）/, V= 3324.67（12） A3, Z = 8, F（000） = 1312, Rint = 0.024 and S = 1.04 for II. We have devised a convenient procedure for the synthesis of fused organic salts resulting from 1：1 proton-transfer, using an amine and a derivative ofbenzenesulfonic acid. The synthesized salts have a number of applications ranging from their consumption as eco-friendly solvents and catalysts in organic syntheses, to being used as efficient precursors for the production of sulfa drugs. Structures of compounds 3-chloroanilinium 2,4-dinitrobenzenesulfonate （CA-DNBS） and triethylaminium 2,4,6-trimethylbenzenesulfonate （TEA-TMBS） were determined by single-crystal X-ray diffraction studies and infrared spectroscopy.     

Laser Flash Photolysis on Electron Transfer Reactions between 1,8-Dihydroxyanthraquinone with Adenine and Cytosine

Electron transfer （ET） reactions between 1,8-dihydroxyanthraquinone （DHAQ） and two DNA bases, adenine （A） and cytosine （C）, have been investigated in CH3CN/H20 solution with nanosecond time-resolved laser flash photolysis. After irradiation at 355 nm, the triplet DHAQ is produced via intersystem crossing and reacts with two nucleobases. ET processes for both reactions have been definitely identified, in which two bases play a significant role of electron donor. Based on the measured decay dynamics of various intermediates and the corresponding quenching rates, an initial ET process followed by a secondary proton-transfer reaction is suggested for both the overall reactions. By plotting the observed quenching rate against the concentration of two DNA bases, the bimolecular quenching rate constants are determined as 9.0-10s L/（mol.s） for the 3DHAQ＊＋C reaction and 3.3x10^8 L/（mol.s） for the 3DHAQ＊＋A reaction, respectively.     

Theoretical Investigation on Interaction between Guanine and Luteolin

The interacting patterns of the luteolin and guanine have been investigated by using the density functional theory B3LYP method with 6-31＋G＊ basis set. Eighteen stable structures for the luteolin-guanine complexes have been found respectively. The results indicate that the complexes are mainly stabilized by the hydrogen bonding interactions. Meanwhile, both the number and strength of hydrogen bond play important roles in determining the stability of the complexes which can form two or more hydrogen bonds. Theories of atoms in molecules and natural bond orbital have also been utilized to investigate the hydrogen bonds involved in all the systems. The interaction energies of all the complexes which were corrected by basis set superposition error are 6.04-56.94 kJ/mol. The calculation results indicate that there are strong hydrogen bonding interactions in the luteolin-guanine complexes. We compared the interaction between luteolin and four bases of DNA, and found luteolin-thymine was the strongest and luteolin-adenine was the weakest. The interaction between luteolin and DNA bases are all stronger than luteolin-water.     

Preparation of TiO2 Nanocrystals/Graphene Composite and Its Photocatalytic Performance

TiO2 nanocrystals/graphene （TiO2/GR） composite are prepared by combining flocculation and hydrothermal reduction technology using graphite oxide and TiO2 colloid as precursors. The obtained materials are examined by scanning electron microscopy, transition electron microscopy, X-ray diffraction, N2 adsorption desorption, and ultraviolet-visible diffuse spectroscopy. The results suggest that the presence of TiO2 nanocrystals with diameter of about 15 nm prevents GR nanosheets from agglomeration. Owing to the uniform distribution of TiO2 nanocrystals on the GR nanosheets, TiO2/GR composite exhibits stronger light absorption in the visible region, higher adsorption capacity to methylene blue and higher efficiency of charge separation and transportation compared with pure TiO2. Moreover, the TiO2/GR composite with a GR content of 30% shows higher photocatalytic removal efficiency of MB from water than that of pure TiO2 and commercial P25 under both UV and sunlight irradiation.     

Efficient Synthesis,Crystal Structure and Antibacterial Activity of Two Novel 1,3-Oxazin Derivatives

Two new 1,3-oxazin derivatives, C22H24N2O5(3I) and C19H16N2O5(3II), have been synthesized via an unusual cascade reaction. The attractive aspect of this cascade reaction is that the novel construction of 1,3-oxazine and the direct C-N bond formation from C-C bond can be easily achieved via pyridine-mediated acylation in a one-pot operation. Both compounds have been synthesized and characterized by elemental analysis, IR, NMR spectra and X-ray single-crystal diffraction. Compound 3I crystallizes in monoclinic, space group P21/n with a = 16.282(4), b = 7.4117(18), c = 17.256(5) , β = 103.193(9)°, V = 2027.4(9) 3, Mr = 396.43, Z = 4, Dc = 1.299 g/cm3, F(000) = 840, MoKa radiation(λ = 0.71073 ), the final R = 0.0771 and wR = 0.1582 for 3662 were observed reflections with I 2σ(I). Compound 3II crystallizes in triclinic, space group P1 with a = 7.1265(9), b = 10.1071(13), c = 23.529(3), α = 97.463(9), β = 96.981(9), γ = 94.345(9)°, V = 1600.5(4) 3, Z = 4, Dc = 1.409 g/cm3, F(000) = 736, CuKa radiation(λ = 1.54186 ), the final R = 0.0515 and wR = 0.1241 for 4920 observed reflections with I 2σ(I). The preliminary antibacterial activities of 2 and 3 against E. coli and S. aureus were investigated. The results showed that the inhibiting effect of 3 was higher than that of 2.     

Fe48Co52 Alloy Nanowire Arrays： Effects of Magnetic Field Annealing

The effects of magnetic field annealing on the properties of Fe48Co52 alloy nanowire arrays with various interwire distances （Di=30-60 nm） and wire diameters （Dw=22-46 nm） were investigated in detail. It was found that the array＇s best annealing temperature and crys- talline structure did not show any apparent dependence on the treatment of applying a 3 kOe magnetic field along the wire during the annealing process. For arrays with small Dw or with large Di, the treatment of magnetic field annealing also had no obvious influence on their magnetic performances. However, such a magnetic field annealing constrained the shift of the easy magnetization direction and improved the coercivity and the squareness obviously for arrays with large Dw or with small Di. The difference in the intensity of the effective anisotropic field within the arrays was believed to be responsible for this different variation of the array＇s magnetic properties after magnetic field annealing.     

Improved Photovoltaic Performance of MEH-PPV/PCBM Solar Cells via Incorporation of Si Nanocrystals

We have studied the effect of silicon nanocrystals （SiNCs） as a third component on performance of organic bulk heterojunction solar cells composed of poly[2-methoxy,5-（2＇-ethylhexyloxy）-l,4-phenylene vinylene] （MEH- PPV）：[6,6]-phenyI-C61-butyric acid methyl ester （PCBM） blend film. By adding suitable amounts of SiNCs into MEH-PPV：PCBM blend, the device performance such as external quantum efficiency, short circuit current density （Js（）, and power conversion efficiency （PCE） improved. Incorporation of 2.5% SiNCs in the blend led to 13.6% improvement of Jsc, which in turn resulted in 18% improvement of PCE up to 2.28%. The improved performance was mainly due to the improvements both in the charge generation from the interface of MEH-PPV/SiNCs and the charge collection at the cathode.     

Reaction Mechanism,Synthesis and Characterization of Urea-glyoxal （UG） Resin

The reaction mechanism of glyoxal （G） with urea （U） under weak acid condition was theoretically investigated at PW91/DNP/COSMO of quantum chemistry using density functional theory （DFT） method. The results show that the addition reaction of G with U under the conditions mainly involves the reactions of U with protonated glyoxal （p-G）, protonated 2,2-dihy- droxyacetaldehyde （p-G 1） and protonated bis-hemdiol （p-G2） to form two important carbocation reactive intermediates of C-p-UG and C-p-UG1, and two important hydroxyl compounds of UG and UG1. These compounds play important roles in the formation of UG resin. According to the result of quantum chemical calculation, UG resin was synthesized successfully under weak acid conditions. The UG resin was characterized by matrix assisted laser desorption ionization time of flight mass spectrometry （MALDI-TOF-MS）, ultraviolet and visible spectroscopy （UV-vis）, Fourier transform infrared spectroscopy （FT1R） and nuclear magnetic resonance spectroscopy （13CNMR and 1HNMR）. These instrumental analytical results agree with each other and further confirm the addition reaction pathway of glyoxal with urea proposed by quantum chemical calculation.     

Time-dependent Density Functional-based Tight-bind Method Efficiently Implemented with OpenMP Parallel and GPU Acceleration

The time-dependent density functional-based tight-bind （TD-DFTB） method is implemented on the multi-core and the graphical processing unit （GPU） system for excited state calcu-lations of large system with hundreds or thousands of atoms. Sparse matrix and OpenMP multithreaded are used for building the Hamiltonian matrix. The diagonal of the eigenvalue problem in the ground state is implemented on the GPUs with double precision. The GPU- based acceleration fully preserves all the properties, and a considerable total speedup of 8.73 can be achieved. A Krylov-space-based algorithm with the OpenMP parallel and CPU acceleration is used for finding the lowest eigenvalue and eigenvector of the large TDDFT matrix, which greatly reduces the iterations taken and the time spent on the excited states eigenvalue problem. The Krylov solver with the GPU acceleration of matrix-vector product can converge quickly to obtain the final result and a notable speed-up of 206 times can be observed for system size of 812 atoms. The calculations on serials of small and large systems show that the fast TD-DFTB code can obtain reasonable result with a much cheaper computational requirement compared with the first-principle results of CIS and full TDDFT calculation.     

Synthesis,Structure and Biological Activity of 5-Benzyl-4-amino-1,2,4- triazole-3-thione Schiff Base

A novel Schiff base was synthesized via 5-benzyl-4-amino-1,2,4-triazole-3-thione with 3-phenoxy-benzaldehyde under refluxing. The structure was characterized by elemental analysis, IR, 1H NMR, ESI-MS and single-crystal X-ray diffraction. This compound crystallizes in monoclinic, space group P21 /c with a = 16.0289(16), b = 5.8022(6), c = 20.542(2), β = 95.667(2)o, C22 H18 N4 OS, Mr = 386.46, V = 1901.1(3)3, Z = 4, Dc = 1.347 g/cm3, F(000) = 804, μ = 0.191 mm-1, the final R = 0.0453 and wR = 0.1307 for 2456 observed reflections with I 2σ(I). The crystal packing of the compound is stabilized by classical intermolecular N–H···S hydrogen bonds. Furthermore, the biological activity to four vegetable pathogens has been tested. The title compound exhibited good fungicidal activities to Gibberlla nicotiancola.     

Two New Cu(Ⅱ) Coordination Polymers Based on 2,5-Furandicarboxylic Acid and 2,2'-bipyridine:Synthesis and Crystal Structure

Two new Cu(Ⅱ) coordination polymers,[Cu(FDA)(BPY)(H2O)]n(1) and {[Cu(FDA)(BPY)(H2O)]·2H2O}n(2)(H2FDA = 2,5-furandicarboxylic acid,BPY = 2,2-bipyridine),have been synthesized and structurally characterized by single-crystal X-ray diffraction as well as elemental analysis and IR.Compound 1 crystallizes in monoclinic,space group P21/c,with a = 7.5915(15),b = 8.4050(17),c = 24.204(6) ,β = 99.05(3)°,V = 1525.1(6) 3,Dc = 1.706 g/cm3,C16H12CuN2O6,Mr = 391.82,F(000) = 796,μ(MoKα) = 1.470 mm–1,Z = 4,R = 0.0633 and wR = 0.1059 for 2389 observed reflections(I 2σ(I)),R = 0.0738,and wR = 0.1098 for all data.Complex 2 belongs to triclinic space group P1 with a = 8.8660(18),b = 8.9112(18),c = 12.525(3) ,α = 88.41(3),β = 69.38(3),γ = 66.95(3)°,V = 845.2(3) 3,Dc = 1.681 g/cm3,C16H16CuN2O8,Mr = 427.85,F(000) = 438,μ(MoKα) = 1.342 mm–1,Z = 2,R = 0.0290 and wR = 0.0690 for 2767 observed reflections(I 2σ(I)),R = 0.0329 and wR = 0.0706 for all data.Complexes 1 and 2 are both coordination polymers with one-dimensional chain structures bridged by the protonated FDA ligands,which are assembled into three-dimensional supramolecular structures through hydrogen bonding interactions and π-π packing interactions between the chains.     

Structure of Co-crystals Formation from lmidazolium and Aromatic Ligands

In this study, two new co-crystals based on rigid imidazolium ligand(2,2'-((1,1'-biphenyl)-4,4'-diyl)bis(2H-imidazo[1,5-a]pyridine-4-ium) hexafluorophosphate(L)) and 4,4'-bipyridine(Bpy) and benzene(Ben), formulated as L(Bpy)0.5(co-crystal 1) and L(Ben)(co-crystal 2), were obtained. Crystal data for 1: P1 space group with a = 10.921(4), b = 16.998(6), c = 17.666(6), α = 95.720(7), β = 104.272(7), γ = 93.340(6)°, V = 3150.5(19) 3 and Z = 2; and crystal data for 2: monoclinic C2/m space group with a = 25.90(2), b = 9.631(9), c = 6.371(6), β = 95.26(2)°, V = 1583(2) 3 and Z = 2. Co-crystal 1 was dependent on hydrogen bonds and π...π stacking, while only hydrogen bonds are present in 2. Two new co-crystals were characterized by IR, NMR spectra, thermogravimetric and ultraviolet absorption analyses.     

State-to-state Photoionization Dynamics of Vanadium Nitride by Two-color Laser Photoionization and Photoelectron Methods

We have conducted a two-color visible-ultraviolet （VIS-UV） resonance-enhanced laser pho- toionization and pulsed field ionization-photoelectron （PFI-PE） study of gaseous vana- dium mononitride （VN） in the total energy range of 56900-59020 cm-1. The VN molecules were selectively excited to single rotational levels of the intermediate VN（D3H0, v＇=0） state by using a VIS dye laser prior to photoionization by employing a UV laser. This two-color scheme allows the measurements of rovibronically selected and re- solved PFI-PE spectra for the VN＋（X2A; v＋=0, 1, and 2） ion vibrational bands. By simulating the rotationally resolved PFI-PE spectra, J＋=3/2 is determined to be the lowest rotational level of the ground electronic state, indicating that the symmetry of the ground VN＋ electronic state is 2A3/2. The analysis of the PFI-PE spectra for VN＋ also yields accurate values for the adiabatic ionization energy for the formation of VN＋（X2A3/2）, IE（VN）=56909.5＋0.8 cm-1 （7.05588±0.00010 eV）, the vibrational fre- quency wc＋=1068.0±0.8 cm-1, the anharmonicity constant wc＋Xe＋=5.8±0.8 cm-1, the rotational constants Be＋=0.6563±0.0005 cm-1 and ae＋=0.0069±0.0004 cm-1, and the equi-librium bond length, re＋=1.529A, for VN＋（X2A3/2）; along with the rotational constants Bc＋=0.6578i0.0028 cm-1 and a＋=0.0085±0.0028 cm-1, and the equilibrium bond length re＋=1.527A for VN＋（X2As/2）, and the spin-orbit coupling constant A=153.3±0.8 cm-1 for VN＋（X2/k5/2,3/2）. The highly precise energetic and spectroscopic data obtained in the present study are valuable for benchmarking the predictions based on state-of-the-art ab initio quantum calculations.     

Synthesis, Crystal Structure,and Antioxidant and Antibacterial Activities of 3,5-Dihydroxy-N＇-（4-nitrobenzylidene）benzohydrazide

A new compound, 3,5-dihydroxy-N＇-（4-nitrobenzylidene）benzohydrazide （I）, has been synthesized and characterized by single-crystal X-ray diffraction. The title compound crystallizes in the monoclinic system, space group P21/c with a = 9.632（12）, b = 12.256（15）, c = 11.425（14） A, β = 105.306（11）°, Z = 4, V = 1301（3） A3, Dc = 1.538 g/cm3, F（000） = 704,μ = 0.276 and S = 1.011. The final R = 0.0444 and wR = 0.1186 for 3808 observed reflections with I〉 20（I）. We used methods such as ABTS, DPPH assays and in vitro hydroxyl radical scavenging experiment to assess the in vitro antioxidant activity of the new compound, and found that its IC50 value was 48.59 μg/mL for scavenging ABTS radicals, 48.04 μg/mL for scavenging DPPH radicals, and 1.03 mg/mL for scavenging hydroxyl radicals, indicating that it had a good in vitro antioxidant activity. We also test the antibacterial activities of this compound against three bacteria, and it showed considerable antibacterial activity against S.aureus. The MIC values of S.aureus, K.pneumoniae and P. aeruginosa are respectively 0.156, 0.625 and 1.25 mg/mL.     

Effects of Non-specific and Specific Solvation on Adsorption of BPTI on Au Surface： Insight from Molecular Dynamics Simulation

Proteins adsorption at solid surfaces are of paramount important for many natural processes. However, the role of specific water in influencing the adsorption process has not been well understood. We used molecular dynamics simulation to study the adsorption of BPTI on Au surface in three water environments （dielectric constant model, partial and full solvation models）. The result shows that a fast and strong adsorption can occur in the dielectric environment, which leads to significant structure changes, as confirmed by great deviation from the crystal structure, largely spreading along the Au surface, rapid lose in all secondary structures and the great number of atoms in contact with the surface. Compared to the dielectric model, slower adsorption and fewer changes in the calculated properties above are observed in the partial solvation system since the specific water layer weakens the adsorption effects. However, in the partial solvation system, the adsorption of polar Au surface causes a significant decrease in the specific hydration around the protein, which still results in large structure changes similar to the dielectric system, but with much less adsorption extent. Enough water molecules in the full solvation system could allow the protein to rotate, and to large extent preserve the protein native structure, thus leading to the slowest and weakest adsorption. On the whole, the effects of non-specific and specific solvation on the protein structure and adsorption dynamics are significantly different, highlighting the importance of the specific water molecule in the protein adsorption.     

Fabrication of Monodisperse ＂Core-Satellite＂ Nanostructures by DNA-Programming： a Novel Class of Superstructured Building Blocks for Hierarchical Nanoassembly

Monodisperse nanoparticle assembly with tunable structure, composition and properties can be taken as a superstructured building block for the construction of hierarchical nanostruc tures from the bottom up, which also represents a great challenge in nanotechnology. Here we report on a facile and controllable method that enables a high yield fabricatioa of uniform gold nanoparticle （AuNP） coresatellites with definable number （in average） of the satellite particles and tunable coretosatellite distance. The formation of the coresatellite nanostruc tures is driven by programmable DNAbasepairing, with the resulting nanocomplexes being isolatable via gel electrophoresis. By rationally controlling the DNA coverages on the core and shell particles, high production yields are achieved for the assembly/isolation process. As well, benefiting from a minimum DNA coverage on the satellite AuNPs, a strong affinity is observed for the asprepared coresatellites to get adsorbed on proteincoated graphene ox ide, which allows for a twodimensional hierarchical assembly of the coresatellite structures. The resulting hierarchical nanoassemblies are expected to find applications in various areas, including plasmonics, biosensing, and nanocatalysis. The method should be generalizable to make even more complicated and higherorder structures by making use of the structural programmability of DNA molecules.