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.     

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.     

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.     

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.     

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.     

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.     

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.     

Synthesis,Crystal Structure and Anticoagulant Activity of 5-Chloro-N-[[（5S）-2-oxo-3-[4-（2- oxopyridin-1 （2H）-yl）phenyl] oxazolidin-5- yl] methyl] thiophene-2-carboxamide①

The title compound(zifaxaban 2, C20H16ClN3O4 S, Mr = 429.87) was synthesized and its crystal structure was determined by single-crystal X-ray diffraction. Zifaxaban crystallizes in monoclinic, space group P21 with a = 5.7900(12), b = 13.086(3), c = 12.889(3) A, β = 100.86(3)°, V = 959.1(3) A3, Z = 2, Dc = 1.489 g/cm3, F(000) = 444, μ = 0.342 mm-1, the final R = 0.0320 and wR = 0.0640 for 2717 observed reflections(I 2σ(I)). The absolute configuration of the stereogenic center in the title compound was confirmed to be S by single-crystal X-ray diffraction. Four existing intermolecular hydrogen bonds help to stabilize the lattice and the molecule in the lattice to adopt an L-shape conformation. Zifaxaban was slightly more active than rivaroxaban 1 in in vitro assay against human FXa and therefore is promising as a drug candidate.     

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.     

Photoionization and Dissociative Photoionization Study of Cholesterol by I R Laser Desorption/Tunable Synchrotron VUV Photoionization Mass Spectrometry

Elementary cholesterol was analyzed with IR laser desorption/tunable synchrotron vacuum ultraviolet photoionization mass spectrometry. An exclusive molecular ion of cholesterol is observed by near threshold single-photon ionization with high efficiency. Fragments are yielded with the increase of photon energy. The structures of various fragments are determined with commercial electron ionization time-of-flight mass spectrometry. Dominant fragmentation pathways are discussed in detail with the aid of ab initio calculations.     

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.     

Synthesis,Crystal Structure and MMCT Property of a New Mixed-valence Cyanide-bridged Binuclear Complex

A new mixed-valence cyanide-bridged complex, Br3Fe(μ-NC)RuBr(dppm)2(dppm = bis(diphenylphosphino)methane), was obtained through the reaction between trans-(dppm)2ClRuCN and FeBr3. Its crystal structure was characterized. Electronic absorption spectra indicate the existence of metal-to-metal charge transfer(MMCT) and this complex is Class Ⅱ mixed valence complexes according to the classification of Robin and Day. Magnetic analysis shows it is paramagnetic.     

Three Inorganic-organic Composite Polyoxotungstates： Syntheses,Characterization and Structures of [Cu（2,2＇-bpy）2]5[α-PW11.5Cu0.5O40]·2H2O, [Co（2,2＇-bpy）2（N3）2]4H3[α-PW12O40]·3H2O and [Cu（2,2＇-bpy）2（4,4＇-bpy）]2[α-GeW12O40]-4H2O

Three new inorganic-organic composite polyoxotungstates [Cu（2,2＇-bpy）2]5[α-PW11.5Cu0.5O40]·2H2O 1, [Co（2,2＇-bpy）2（N3）2]4H3[α-PW12O40]·3H2O 2 and [Cu（2,2＇-bpy）2（4,4＇-bpy）]2[α-GeW12O40]-4H2O 3 （2,2＇-bpy = 2,2＇-bipyridine, 4,4＇-bpy = 4,4＇-bipyridine） have been hydrothermally synthesized and structurally characterized. 1 crystallizes in the orthorhombic space group Pna21 with a = 27.847（3）, b = 21.597（2）, c = 20.1179（19）A, V= 12099（2）A^3, Z= 4, GOF= 1.038, R = 0.0427 and wR = 0.1035; 2 belongs to the triclinic space group P1^- with a = 12.31150（10）, b = 16.1954（4）, c = 19.36290（10）A, α = 99.366（11）, β =105.168（8）, γ = 111.836（8）°, V = 3309.98（9）A3, Z = l, GOF = 1.024, R = 0.0739 and wR = 0.2216; and 3 crystallizes in the monoclinic space group P21/n with a = 12.858（4）, b = 20.943（6）, c = 15.598（5）A, β = 102.338（5）°, V= 4103（2）A3, Z = 2, GOF = 1.026, R = 0.0557 and wR = 0.1316. The common structural features of 1-3 are that their molecular structures all consist of a saturated a-Keggin polyoxoanion and several discrete metal-organic moieties. Intriguingly, 2 and 3 are composed of metal-organic coordination moieties with two mixed ligands.     

Asymmetric Synthesis, Antifungal Activity and Molecular Modeling of Iodiconazole Isomers

Iodiconazole is a novel antifungal agent that was developed in its racemic form. In order to investigate the ef- fects of the chiral center on the antifungal activity, R- and S-isomers of iodiconazole were prepared on the basis of the asymmetric Sharpless epoxidation. （S）-Iodiconazole was proved to have better antifungal activity than the （R）- isomer. The binding modes of the two isomers with lanosterol 14~z-demethylase were clarified by molecular dock- ing.     

Synthesis,Crystal Structure,and Photoluminescent and Semiconductive Properties of [La（C6NO2Hs）3-（H2O）2]2n·（nH5O2）（nHgCl5）（2nHgCl4）·（2nH2O）

A new heterometallic 4f-5d inorganic-organic metal-isonicotinic acid complex [La（C6NO2Hs）3-（H2O）2]2n·（nH5O2）（nHgCl5）（2nHgCl4）·（2nH2O） 1 has been synthesized via hydro- thermal reaction and structurally characterized. Complex 1 crystallizes in the space group C21c of monoclinic system with four formula units in a cell： a = 24.140（7）, b = 20.884（7）, c = 15.462（2）A, fl = 127.46（1）°, V = 6187（3）A3, C36HaTCl13Hg3La2N6020, Mr = 2224.24, Dc = 2.388 g/cm3, Z = 4, T = 293（2） K, μ（MoKa） = 9.401 mm-1, F（000） = 4160 and RIwR = 0.0376/0.0636 for 4130 observed reflections （I 〉 20（/）） and 5617 unique reflections. Complex 1 is characteristic of a one-dimensional polycationic chain-like structure. Photoluminescent investigation reveals that the title complex displays interesting emissions in violet and orange regions. The luminescence spectra show stronger orange emission than violet emission. Optical absorption spectra of 1 reveal the presence of a wide optical bandgap of 3.41 eV.     

Bonding of Hydroxyl and Epoxy Groups on Graphene： Insights from Density Functional Calculations

Density functional theory and GGA-PW91 exchange correlation function were performed to simulate the bonding behavior of hydroxyl and epoxy groups on the graphene surface. We compared the different binding energies for two epoxy groups, as well as one hydroxyl group and one epoxy group on all possible positions within a 6-fold ring, respectively. The calculated results suggest that two oxygen-containing groups always tend to bind with the neighboring carbon atoms at the opposite sides. Moreover, two hydroxyl groups on the meta position are unstable, and one of the hydroxyl groups easily migrates to the para position. In contrast to the disperse arrangement, the aggregation of multiply hydroxyl groups largely enhances the binding energy of every hydroxyl group. It is worth noting that the binding sites and hydrogen bonds play an important role in stability. Our work further points out the number of oxygen-containing groups and the location of oxide region largely influence the electronic properties of graphene oxide.     

Synthesis,Crystal Structure and Antifungal Activities of 3-Methyl-l-（4-methylphenyl）-4- （N-4-trifluoromethylphenyl）-aminomethyl- 5-（4-methoxyphenylthio）-lH-pyrazole

The title compound 3-methyl-l-（4-methylphenyl）-4-（N-4-trifluoromethylphenyl） aminomethyl-5-（4-methoxyphenylthio）-lH-pyrazole has been synthesized via a four-step reaction and characterized by IR, 1H NMR, elemental analysis and X-ray crystallography. The compound crystallizes in monoclinic, space group P21/c with a = 8.7170（15）, b = 18.355（3）, c = 15.292（3） A, fl = 103.445（3）°, V= 2379.7（7） A3, Dc = 1.350 g/cm3, Z = 4, p = 0.184, F（000） = 1008, and the final R = 0.0491 and wR = 0.1339 for 4160 observed reflections （I 〉 2a（/））. The results demonstrate that there is a face-to-face π-π stacking interaction between one benzene ring （C（19）-C（24）） and another （C（I 3）-C（! 8）） at a plane-plane distance of 3.3539 A. The ring normal and vector between the ring centroids form an angle of 18.2° up to the centroid-to-centroid distance of 3.5273 A. The crystal structure is stabilized by the intermolecular hydrogen bond of N（3）-H（3A）...N（2） （symmetry code： A -x＋l, -y＋l, -z）. The preliminary biological test shows that the title compound has a moderate antifungal activity.