Structural Insights into the Interactions of Digoxin and Na+/K+-ATPase and Other Targets for the Inhibition of Cancer Cell Proliferation

Digoxin is a cardiac glycoside long used to treat congestive heart failure and found recently to show antitumor potential. The hydroxy groups connected at the C-12, C-14, and C-3′a positions; the C-17 unsaturated lactone unit; the conformation of the steroid core; and the C-3 saccharide moiety have been demonstrated as being important for digoxin’s cytotoxicity and interactions with Na⁺/K⁺-ATPase. The docking profiles for digoxin and several derivatives and Na⁺/K⁺-ATPase were investigated; an additional small Asn130 side pocket was revealed, which could be useful in the design of novel digoxin-like antitumor agents. In addition, the docking scores for digoxin and its derivatives were found to correlate with their cytotoxicity, indicating a potential use of these values in the prediction of the cancer cell cytotoxicity of other cardiac glycosides. Moreover, in these docking studies, digoxin was found to bind to FIH-1 and NF-κB but not HDAC, IAP, and PI3K, suggesting that this cardiac glycoside directly targets FIH-1, Na⁺/K⁺-ATPase, and NF-κB to mediate its antitumor potential. Differentially, digoxigenin, the aglycon of digoxin, binds to HDAC and PI3K, but not FIH-1, IAP, Na⁺/K⁺-ATPase, and NF-κB, indicating that this compound may target tumor autophagy and metabolism to mediate its antitumor propensity.     

Spectroscopic and PM5 semiempirical studies of new hydrazone of gossypol with 3,6-dioxaheptylhydrazine

A new hydrazone of gossypol with 3,6-dioxaheptylhydrazine (GHDO) has been synthesised and its structure has been studied by FT-IR, ¹H NMR, ¹³C NMR as well as PM5 semiempirical methods. All the studies have provided clear evidence of the existence of GHDO in the solution in the N-imine–N-imine tautomeric form. The structure and the spectroscopic behaviour of this tautomer are discussed in details. It is shown the structure of GHDO is strongly stabilised by different types of intramolecular hydrogen bonds. In two of them the oxygen atoms of the oxaalkyl chains are also engaged. The strongest intramolecular hydrogen bond is formed between the O₇H proton and N₁₆ atom from the hydrazone group.     

Quantitative analysis of complex amino acids and RGD peptides by X‐ray photoelectron spectroscopy (XPS)

The C 1 s, N 1 s, and O 1 s core level binding energies (BEs) of the functional groups in amino acids (glycine, aspartic acid, glutamic acid, arginine, and histidine) with varied side‐chains and cell‐binding RGD‐based peptides have been determined and characterized by X‐ray photoelectron spectroscopy with a monochromatic Al K_α source. The zwitterionic nature of the amino acids in the solid state is unequivocally evident from the N 1 s signals of the protonated amine groups and the C 1 s signature of carboxylate groups. Significant adventitious carbon contamination is evident for all samples but can be quantitatively accounted for. No intrinsic differences in the XP spectra are evident between two polymorphs (α and γ) of glycine, indicating that the crystallographic differences have a minor influence on the core level BEs for this system. The two nitrogen centers in the imidazole group of histidine exhibit an N 1 s BE shift that is in line with previously reported data for theophylline and aqueous imidazole solutions, while the nitrogen and carbon chemical shifts reflect the unusual guanidinium chemical environment in arginine. It is shown that the complex envelopes of C 1 s and O 1 s photoemission spectra for short‐chain peptides can be analyzed quantitatively by reference to the less complex XP spectra of the constituent amino acids, provided the peptides are of high enough purity. The distinctive N 1 s photoemission from the amide linkages provides an indicator of peptide formation even in the presence of common impurities, and variations in the relative intensities of N 1 s were found to be diagnostic for each of the three peptides investigated (RGD, RGDS, and RGDSC). Copyright © 2013 John Wiley & Sons, Ltd.     

Ultraviolet Reflection Irradiances and Exposures in The Constructed Environment For Horizontal,Vertical and Inclined Surfaces

Ultraviolet (UV) reflection in the urban constructed environment is not well understood for topical issues such as measuring and modeling the received UV exposure due to that UV reflection for outdoor workers. Both predominantly specular and diffuse reflecting surface types have been identified and investigated for the erythemal UV reflection ratio variation due to solar zenith angle and orientation. This paper presents relationships between erythemal UV reflection ratios measured for non‐horizontal and horizontal surfaces, with predominantly specular surface types indicating stronger relationships with solar zenith angles than diffuse reflecting surfaces types. Erythemal UV exposures caused by the same reflecting surface types at three inclinations are also investigated. Non‐horizontal surfaces can increase erythemal UV exposures compared to erythemal UV exposures received from the same horizontal surface by factors of 1.07–1.46 for specific body sites and by 1.01–1.70 for averages of group body sites for zinc aluminium coated steel sheeting.     

Application of Sulfinyl bis(2,4‐dihydroxythiobenzoyl) in the Synthesis of N‐Substituted 2‐Amino‐5‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles

One‐stage synthesis of N‐substituted 2‐amino‐5‐(2,4‐dihydroxyphenyl)‐1,3,4‐thiadiazoles is described. The compounds were prepared by the reaction of the sulfinyl bis(2,4‐dihydroxythiobenzoyl) (STB) with 4‐substituted 3‐thiosemicarbazides. STB was obtained from 2,4‐dihydroxybenzenecarbodithioic acid and thionyl dichloride. The structure of compounds was confirmed by IR, ¹H NMR, ¹³C NMR, and EI‐MS data.     

Liquid crystalline properties of 4‐hexyloxybenzylidene‐4′‐alkyloxyanilines

The liquid‐crystalline polymorphism of the homologous series of 4‐hexyloxybenzylidene‐4′‐alkyloxyanilines is investigated. Basing on the polarization microscopy (POM, TOA), the DSC calorimetry and miscibility studies the following mesophases were detected: nematic, smectic A, smectic C and smectic I. The phase diagrams of the compounds of these series with 4‐hexyloxybenylidene‐4′‐pentylaniline (as the standard of mesophases) show induction of the smectic F mesophases. Their dependence on the alkyl chain length and mole fraction is shown.     

Spontaneous formation of liquid crystalline phases and phase transitions in highly concentrated plasmid DNA

The liquid crystalline (LC) properties of two supercoiled plasmid DNA samples, pBSK (2958 bp) and pGEM (3000 bp), have been studied using polarised light microscopy (PLM), circular dichroism (CD) and UV–Vis spectroscopy. The influence of methods of isolation on plasmid LC behaviour is described, and using PLM we have demonstrated the spontaneous formation of cholesteric fingerprint-like textures. Preliminary studies of LC phase transitions in pGEM show the irreversibility of LC phase formation, as a consequence of changes in the tertiary structure of supercoiled plasmids. Using UV–Vis spectroscopy a hyperchromic effect was observed with increasing temperature. The CD spectra clearly showed structural changes, and probably mismatching of DNA bases, during cooling. Finally, we have observed an irreversible phase transition in plasmid DNA which is very different from that previously reported in linear DNA.     

The kinetics of the E-Z-E isomerisation and liquid-crystalline properties of selected azobenzene derivatives investigated by the prism of the ester group inversion

Two new groups of azobenzene ester derivatives were synthesised: alkyl 4-[4-(nonyloxy)phenyl]diazenyl]benzoates and 4-[4-(nonyloxy)phenyl]diazenyl]phenyl alkanoates. All 35 presented homologues are mesogenic. Moreover, some of the above-mentioned compounds exhibit rich liquid-crystalline polymorphism likewise tetramorphism. During this investigation by the use of polarising optical microscopy, differential scanning calorimetry and X-Ray studies, six types of mesophases were detected: nematic, smectics (A, C, I, F) and G. Furthermore, due to the presence of the photosensitive azo moiety, the E–Z isomerisation reaction is possible. This process, which is initiated by the UV irradiation, causes significant changes in the UV-Vis absorption spectra of investigated compounds. However, the photoisomerisation is a reversible process and in the dark the thermal relaxation of Z isomer takes place. Based on the achieved data, the kinetic constants of the isomerisation and relaxation processes were calculated. It shows that conversion of the ester bond makes some changes in the optical properties. The shift of about 7 nm of the absorbance maximum was observed. Surprisingly, the inversion of the ester group has significant influence on the liquid-crystalline polymorphism replacing one mesophase (for benzoates) into four (for alkanoates).     

SrInGe and EuInGe: new Zintl phases with an unusual anionic network derived from the ThSi(2) structure

Two new isostructural Zintl phases, EuInGe and SrInGe, are obtained from high-temperature reactions of the pure elements in welded Ta tubes. Both ternary phases crystallize in a new structure type in space group Pnma (No. 62), with a = 4.921(1) A, b = 3.9865(9) A, and c = 16.004(3) A for EuInGe; and a = 5.021(1) A, b = 4.0455(9) A, and c = 16.188(4) A for SrInGe. The crystal structures established by single-crystal X-ray diffraction feature zigzag chains of 3-bonded Ge atoms and puckered layers of 4-bonded In atoms. The two structural units are linked into an anionic network with channels composed of 5-membered and 7-membered rings. The channels are filled by the respective divalent cations. The chemical bonding of the anionic [InGe](2)(-) network, derived from a one-electron oxidative distortion of the alpha-ThSi(2) structure, is explained using extended-Hückel band structure calculations. Magnetic measurements indicate that EuInGe exhibits Curie-Weiss paramagnetic behavior above 35 K and antiferromagnetic behavior below 35 K. The calculated effective moment, mu(eff) = 8.11 mu(B), of EuInGe and the diamagnetic behavior of SrInGe are consistent with the oxidation states of Eu(II) and Sr(II), respectively.