Experimental/theoretical electrostatic properties of a styrylquinoline-type HIV-1 integrase inhibitor and its progenitors

We have established that polyhydroxylated styrylquinolines are potent inhibitors of HIV-1 integrase (IN). Among them, we have identified (E)-8-hydroxy-2-[2-(4,5-dihydroxy-3-methoxyphenyl)-ethenyl]-7-quinolinecarboxylic acid (1) as a promising lead. Previous molecular dynamics simulations and docking procedures have shown that the inhibitory activity involves one or two metal cations (Mg2+), which are present in the vicinity of the active center of the enzyme. However, such methods are generally based on a force-field approach and still remain not as reliable as ab initio calculations with extended basis sets on the whole system. To go further in this area, the aim of the present study was to evaluate the predictive ability of the electron density and electrostatic properties in the structure-activity relationships of this class of HIV-1 antiviral drugs. The electron properties of the two chemical progenitors of 1 were derived from both high-resolution X-ray diffraction experiments and ab initio calculations. The twinning phenomenon and solvent disorder were observed during the crystal structure determination of 1. Molecule 1 exhibits a planar s-trans conformation, and a zwitterionic form in the crystalline state is obtained. This geometry was used for ab initio calculations, which were performed to characterize the electronic properties of 1. The electron densities, electrostatic potentials, and atomic charges of 1 and its progenitors are here compared and analyzed. The experimental and theoretical deformation density bond peaks are very comparable for the two progenitors. However, the experimental electrostatic potential is strongly affected by the crystal field and cannot straightforwardly be used as a predictive index. The weak difference in the theoretical electron densities between 1 and its progenitors reveals that each component of 1 conserves its intrinsic properties, an assumption reinforced by a 13C NMR study. This is also shown through an excellent correlation of the atomic charges for the common fragments. The electrostatic potential minima in zwitterionic and nonzwitterionic forms of 1 are discussed in relation with the localization of possible metal chelation sites.     

Spectrophotometric study of the reaction mechanism between DDQ as pi-acceptor and potassium iodate and flucloxacillin and dicloxacillin drugs and their determination in pure and in dosage forms

Two simple and accurate spectrophotometric methods are presented for the determination of beta-lactam drugs, flucloxacillin (Fluclox) and dicloxacillin (Diclox), in pure and in different pharmaceutical preparations. The charge transfer (CT) reactions between Fluclox and Diclox as electron donors and 2,3-dichloro-5,6-dicyano-p-benzoquinone (DDQ) pi-acceptor and potassium iodate via oxidation reduction reaction where the highly coloured complex species or the liberated iodine have been spectrophotometrically studied. The optimum experimental conditions have been studied carefully. Beer's law is obeyed over the concentration range of 2-450 microg ml(-1) for Fluclox and 10-450 microg ml(-1) for Diclox using DDQ reagent and at 50-550 microg ml(-1) for Fluclox and 50-560 microg ml(-1) for Diclox using iodate method, respectively. For more accurate results, Ringbom optimum concentration range is calculated and found to be 6-450 and 15-450 microg ml(-1) for Fluclox and Diclox using DDQ, respectively, and 65-550 and 63-560 microg ml(-1) for Fluclox and Diclox using iodine, respectively. The Sandell sensitivity is found to be 0.018 and 0.011 microg cm(-2) for DDQ method and 0.013 and 0.011 microg cm(-2) for iodate method for Fluclox and Diclox, respectively, which indicates the high sensitivity of both methods. Standard deviation (S.D.=0.01-0.80 and 0.07-0.98) and relative standard deviation (R.S.D.=0.13-0.44 and 0.11-0.82%) (n=5) for DDQ and iodate methods, respectively, refer to the high accuracy and precision of the proposed methods. These results are also confirmed by between-day precision of percent recovery of 99.87-100.2 and 99.90-100% for Fluclox and Diclox by DDQ method and 99.88-100.1 and 99.30-100.2% for Fluclox and Diclox by iodate method, respectively. These data are comparable to those obtained by British and American pharmacopoeias assay for the determination of Fluclox and Diclox in raw materials and in pharmaceutical preparations.     

Remarks on the asymptotic behavior of scalar auxiliary variable (SAV) schemes for gradient-like flows

We introduce a time semi-discretization of a damped wave equation by a SAV scheme with second order accuracy. The energy dissipation law is shown to hold without any restriction on the time step. We prove that any sequence generated by the scheme converges to a steady state (up to a subsequence). We notice that the steady state equation associated to the SAV scheme is a modified version of the steady state equation associated to the damped wave equation. We show that a similar result holds for a SAV fully discrete version of the Cahn-Hilliard equation and we compare numerically the two steady state equations.     

PopGen: population-based recruitment of patients and controls for the analysis of complex genotype-phenotype relationships

OBJECTIVE: Patient samples used for mapping complex human disease genes are unlikely to be representative of the phenotype spectrum of the respective population as a whole. On the other hand, most ongoing prospective studies are probably too small for evaluating polygenic disease markers. DESIGN: Precise estimates of population-specific genotypic risks can be obtained efficiently through the complete ascertainment of patients in a geographically confined area. The PopGen project uses the most northern part of Germany as a target region for such a pursuit. RESULTS: PopGen currently pursues recruitment, sampling and processing activities in close collaboration with a multitude of clinical partners, covering cardiovascular, neuropsychiatric and environmental diseases. CONCLUSION: PopGen has successfully established itself as a large-scale genetic epidemiological project of international recognition.     

Interior Sphere Condition for the Graph of a Multifunction

For a given multifunction, we provide proximal differentiability condition under which the equivalence between the interior sphere condition of each value of the multifunction and the interior sphere condition of its graph holds.     

Rapid Photoactuation of a DNA Nanostructure using an Internal Photocaged Trigger Strand

A reconfigurable DNA nano‐tweezer is reported that can be switched between a closed and open state with a brief pulse of UV light. In its initial state, the tweezer is held shut using a hairpin with a single‐stranded poly‐A loop. Also incorporated in the structure is a poly‐T trigger strand bearing seven photocaged residues. Upon illumination with 365 nm light, the cages are removed and the trigger strand hybridizes to the loop, opening the tweezer and increasing the distance between its arms from 4 to 18 nm. This intramolecular process is roughly 60 times faster than adding an external trigger strand, and provides a mechanism for the rapid interconversion of DNA nanostructures with light.     

Spectroscopic investigation of the donor-acceptor interaction between o-phenylenediamine and tetracyanoethylene in dichloromethane

The interaction between the electron donor o-phenylenediamine (o-phendn) and the pi-acceptor tetracyanoethylene (TCNE) has been investigated spectrophotometrically in dichloromethane at 25 degrees C. The results indicate that the reaction proceeds via two major steps. The formation of the 1:2 charge-transfer complex [(o-phendn)(2), (TCNE)(4)] in which two o-phenylenediamine molecules undergoes slow N-substitution by one TCNE forming the final reaction product 2,2-di-o-aminoaniline-1,1-dicyanoethylene and 2HCN molecules. The reaction was studied using electronic, infrared, photometric titration and cyclic voltametric measurements. A general mechanism for the reactions is proposed.     

Radiochemical measurement of <Superscript>237</Superscript>Np in a solution of mixed radionuclides: Experiences in chemical separation and alpha-spectrometry

A radiochemical procedure is described for the measurement of 0.1 Bq ²³⁷Np in a solution containing similar activity concentrations of Th, U, Pu and Am as well as activity concentrations of ⁶⁰Co, ⁹⁰Sr and ¹³⁷Cs one hundred times higher. A tracer of ²³⁹Np (milked from ²⁴³Am) was used as an isotopic spike for chemical yield determination. The relationship between gamma-counting geometries for ampoule (liquid) and NdF₃ (solid) ²³⁹Np sources was established so that Np chemical yields could be measured by a comparative method. Efficiencies of alpha-spectrometers for ²³⁷Np in NdF₃ sources were measured by a bootstrap technique. Two sets of experiments were designed and used to test out the procedure.     

Crystal structures and physico-chemical properties of Zn(II) and Co(II) tetraaqua(3-nitro-4-hydroxybenzoato) complexes: Their anticonvulsant activities as well as related (5-nitrosalicylato)–metal complexes

Purposes of these studies were to synthesize Zn(II) and Co(II) complexes of 3-nitro-4-hydroxybenzoic acid, determine their structures through X-ray crystallography, and obtain their anticonvulsant activities. Thermogravimetric, differential scanning calorimetry, impedance of aqueous solutions and magnetic properties analyses were also determined. Anticonvulsant and related activities of these complexes as well as Zn(II), Co(II), Ni(II) and Mg(II) (5-nitrosalicylato) complexes were determined by the National Institutes of Health, Antiepileptic Development Program. Results of these analyses are presented to document unique bonding features and physical properties of these compounds and their anticonvulsant activities. It is concluded that these compounds have chemical and physical properties that can be used to account for their anticonvulsant activities.     

Theoretical study of selenium and tellurium impurities in (ZnO)6 clusters using DFT and TDDFT

Zinc oxide (ZnO) nanostructures have attracted much interest due to their potential applications in various fields including optoelectronics, glass industries, and solar cells. These compounds hold the promise of creating new materials that can advance energy technologies. In this work, a series of (ZnO)₆ clusters with selenium and tellurium applied as substitutional impurities has been studied. The investigated structures have been produced through the doping of (ZnO)₆ clusters by replacing an oxygen atom with a selenium or a tellurium atom at each time. The ground state geometric parameters of (ZnO)₆ structures, containing selenium or tellurium atoms as substitutional impurities, were calculated using density functional theory (DFT) with B3LYP and LanL2DZ basis set. Excited state energies and absorption wavelengths were computed using time‐dependent‐DFT (TDDFT). For the calculation of emission wavelengths, Hartree–Fock configuration interaction singles (HF/CIS) has been used in order to perform the excited state geometry optimization. This work led to some important results that can be helpful for developing novel THz sensitive materials and imaging detectors that may be an alternative to x‐rays detectors for radiology as well as for the development of solar cells and electroluminescent diodes. Zinc oxide (ZnO) nanostructures have attracted growing interest due to their potential applications in many technological fields, including optoelectronics, the glass industry, and energy. The presence of impurities, in particular selenium and tellurium, in ZnO‐based clusters can affect their structural and spectroscopic properties. Some of these doped nanostructures have favorable Terahertz emission characteristics that make them good candidates for applications in biology and medicine.