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.     

Modelling the circularly and linearly polarised spectrum of [Ni(en)3]2+

The relative intensity and band shapes of the low energy spin-allowed transitions in the linearly polarised and circular dichroism spectrum of [Ni(en)(3)](2+) have been calculated using a time-dependent density functional theory approach. The effect of the trigonal ligand-field is minimal and no splitting of the bands is predicted by the simulations or observed experimentally. The 'd-d' transitions of the [Ni(en)(3)](2+) ion are electric dipole allowed but gain much of their intensity through Herzberg-Teller vibronic coupling. Its CD spectrum is dominated by the low energy band, which gains its rotatory strength through the magnetic dipole-allowed character of the parent octahedral transition and the electric dipole character due to the trigonal field. The simulation of the spectrum incorporates the contribution from all inducing vibrational modes with significant involvement of the {NiN(6)} unit. Vibrations which are centred on the chelate rings are not important in generating intensity, reflecting the localised d-d' character of the transitions. Simulated linearly polarised and circular dichroism spectra of such an open-shell system are presented for the first time and predict the essential elements of the experimental spectra.     

Potential of Supported Copper and Potassium Oxide Catalysts in the Combustion of Carbonaceous Particles

Different oxide carriers (TiO₂ and ZrO₂) as supports for low amounts of Cu²⁺ and K⁺ species (2 wt % as equivalent oxide) were tested in the catalytic oxidation of carbon black. The K-Cu/oxide catalysts were shown to have a lower soot combustion temperature than K/oxide, Cu/oxide, and pure oxide carriers. The K-Cu/ZrO₂ catalyst was found to be the most active; it exhibited activity in a loose contact nearly similar to that obtained in a tight contact mode. Physicochemical characterization by EPR, XPS, and TPR revealed the interaction of K⁺ species with Cu²⁺ species and the ZrO₂ carrier in K-Cu/ZrO₂ as well as a strongly distorted Cu²⁺ species on the ZrO₂ surface. The potassium ions ensure promoting effects towards the contact between the carbon black and the catalyst surface. Although potassium ions were found to lower the reducibility of the cupric oxide species, the oxidation rate of carbon black increased in the presence of K/oxide and K-Cu/oxide.     

Optimization of a molecular mechanics force field for type-II polyoxometalates focussing on electrostatic interactions: a case study

In this study, we have focussed on type-II polyanions such as [M(7)O(24)](6-), and we have developed and validated optimized force fields that include electrostatic and van der Waals interactions. These contributions to the total steric energy are described by the nonbonded term, which encompasses all interactions between atoms that are not transmitted through the bonds. A first validation of a stochastic technique based on genetic algorithms was previously made for the optimization of force fields dedicated to type-I polyoxometalates. To describe the new nonbonded term added in the functional, a fixed-charged model was chosen. Therefore, one of the main issues was to analyze that which partial atomic charges could be reliably used to describe these interactions in such inorganic compounds. Based on several computational strategies, molecular mechanics (MM) force field parameters were optimized using different types of atomic charges. Moreover, the influence of the electrostatic and van der Waals buffering constants and 1,4-interactions scaling factors used in the force field were also tested, either being optimized as well or fixed with respect to the values of CHARMM force field. Results show that some atomic charges are not well adapted to CHARMM parameters and lead to unrealistic MM-optimized structures or a MM divergence. As a result, a new scaling factor has been optimized for Quantum Theory of Atoms in Molecules charges and charges derived from the electrostatic potential such as ChelpG. The force fields optimized can be mixed with the CHARMM force field, without changing it, to study for the first time hepta-anions interacting with organic molecules.     

Thermal Analysis,EPR and XPS Study of Vanadyl(IV) Oxalate Behavior on the Ceria Surface

The thermal decomposition of vanadyl oxalatesupported on CeO₂ solid in a flow of dried air was analysed by thermogravimetry (TG) and differential scanning calorimetry (DSC) from room temperature up to 350°C. TG and DSC results have demonstrated that after the impregnation of CeO₂ solid by a vanadyl oxalate solution, cerium and vanadium(V) oxalates were evidenced. This latter compound seems attached to cerium(III) of the partial reduced CeO₂ phase. This result was confirmed with the electron paramagnetic resonance(EPR) and X-ray photoelectron spectroscopy (XPS) techniques. This revised version was published online in July 2006 with corrections to the Cover Date.     

Optimization of a molecular mechanics force field for polyoxometalates based on a genetic algorithm

A stochastic technique based on genetic algorithms was implemented to develop new force fields by optimizing molecular mechanics (MM) parameters. These force fields have been optimized for inorganic compounds such as polyoxometalates (POMs) and especially for type‐I polymolybdate and polytungstate clusters. Focussing on the methodology of the development of the force fields, they were tested for the prediction of structural parameters, comparing the MM optimized structures with the geometry obtained after an optimization based on density functional theory. Results show that the genetic algorithm converges toward an optimum combination of parameters which successfully reproduces POMs structures with a high degree of accuracy. © 2010 Wiley Periodicals, Inc. J Comput Chem, 2011     

Synthesis and inclusion ability of a bis-β-cyclodextrin pseudo-cryptand towards Busulfan anticancer agent

The synthesis of a C₂-symmetric receptor including two β-cyclodextrins connected by urea linkers to a chiral diaza-crown ether organising platform is reported. This molecular system, long thought to be a potent selective carrier for chiral/achiral organic/inorganic guests at the supramolecular level, was found to be an efficient complexing tool towards the Busulfan anticancer agent.     

Electronic properties of 3,3'-dimethyl-5,5'-bis(1,2,4-triazine): towards design of supramolecular arrangements of N-heterocyclic Cu(I) complexes

A new efficient and safe synthesis of 3,3'-dimethyl-5,5'-bis-(1,2,4-triazine) is presented. The electron-density distribution and electrostatic properties (charge, electrostatic potential) of this molecule were analyzed. These properties were derived from a high-resolution single-crystal X-ray diffraction experiment at 100 K and compared to the results obtained from ab initio DFT quantum-mechanical calculations. Comparisons of its electrostatic potential features and integrated atomic charges (quantum theory of atoms in molecules, QTAIM) have been made with those of related molecules such as bipyrimidine ligands. Two methods were used to derive integrated charges: one is based on the conventional analytical procedure and the second uses a steepest-ascent numerical algorithm. Excellent agreement was obtained between these two methods. Charges and electrostatic potential were used as predictive indices of metal chelation and discussed in the light of complexation abilities of the title compound and related molecules. The crystal structure of a Cu(I) complex of 3,3'-dimethyl-5,5'-bis(1,2,4-triazine) is reported here. In the solid state, this complex forms a three-dimensional multibranch network with open channels in which counterions and solvent molecules are located. This architecture involves both cis and trans isomers of the title compound.     

Comparison of alkali-promoted ZrO2 catalysts towards carbon black oxidation

The effect of alkali metals deposition on zirconia has been studied in the oxidation of carbon black, considered as a model of diesel soot. The study of the influence of alkali content and alkali precursor was undertaken for K/ZrO₂, evidencing a better activity for a catalyst prepared with an atomic ratio K/Zr = 0.14 and from a nitrate precursor. Using the latter preparation conditions, alkali/ZrO₂ are found to be active in the oxidation of carbon black according the sequence ZrO₂ < Li/ZrO₂ < Na/ZrO₂ < K/ZrO₂ < Rb/ZrO₂ < Cs/ZrO₂. Alkali metals have an influence on the tetragonal–monoclinic crystalline modification. Alkali metals ions with low size tend to stabilize the tetragonal ZrO₂ phase whereas those with higher ionic radius favour the tetragonal–monoclinic modification. Fourier transform-infrared spectroscopy (FTIR) and temperature programmed reduction (TPR) measurements show that the catalytic activity partially depends on the presence of nitrate species stabilized in alkali/ZrO₂ even after calcination treatment at 600 °C. Nitrate species are more stable in the presence of alkali with high ionic radius than those of low size.