New designs for inhibitors of the NF-κB: DNA binding

We present a series of new inhibitors of the association between nuclear factor kappa B (NF-B) and the corresponding B site in DNA. They were designed using the lead compound 15-deoxy-^12,14 -prostaglandin J₂ (PGJ2), which is a natural product with demonstrated inhibitory efficiency for this system. First, the binding mode of PGJ2 to NF-B was unraveled by GOLD docking calculation. Subsequently, substitutions were made to PGJ2 to optimize its association with NF-B. Care was taken not to strongly increase the reactivity of the new compounds, and to keep the overall shape, size and hydrophilicity of the lead compound, which should render them a similar bioavailability. Molecular mechanics calculations were performed to decide on the suitability of the substitutions, and to evaluate the energies of association with NF-B. Density functional theory calculations were performed also to study the overall reactivity of the substituted drugs towards NF-B. Important general conclusions were obtained, concerning the improvement of these natural inhibitors; namely, a set of rational methodologies were deduced to improve the association between the PGJ2 derivatives and NF-B, and their efficiency demonstrated by generating a set of substituted complexes, some of them with a very much increased affinity for NF-B, opening new doors to enlarge the therapeutic capabilities of this class of drugs.     

Spectroscopic and electrochemical studies on (2-hydroxypicolinate)-bis(2,2′-bipyridine)ruthenium(II) and related complexes

Summary The synthesis, spectra and electrochemistry of [Ru(bipy)₂-(picOH)]⁺ and -picO-[Ru(bipy)₂]₂ ²⁺ (bipy = 2,2-bipyridine and picOH = 3-hydroxypicolinate ion) are described. The spectroscopic properties in the visible region are dominated by the intense Ru bipy chargetransfer transitions. In the binuclear complex, the two [Ru(bipy)₂L]²⁺ moieties are nonequivalent, exhibiting E _1/2 = 0.69 and 1.20 V versus s.h.e. The partially oxidized species exhibits a weak intervalence transfer band at 1085 nm, and is consistent with a Robin-Day class II mixed valence complex.     

Potentiometric, luminescence and NMR study of the interaction of Eu with glyceryl phosphates

Complexation of europium(III) with glyceryl-1- and -2-phosphates has been studied by metal ion luminescence, ¹H and ¹³C NMR spectroscopy and potentiometry. From the luminescence and NMR studies, the formation of a 1:1 inner-sphere complex, in which the glyceryl phosphate is directly bound to the metal, is confirmed. Similar apparent binding constants at pH 2 were obtained by the three methods. Values obtained by NMR at pH 2 are 53 M⁻¹ and 12 M⁻¹ for glyceryl-1- and -2-phosphate, respectively. By comparison with literature data on related systems it is suggested that the ligands bind through the phosphate group. To obtain structural information from the NMR data, complexation has also been studied with the lanthanide ions Dy(III), Er(III) and Gd(III) using both chemical shift and relaxation data. From this, metal-proton distance ratios have been calculated. Comparison of ¹H and ¹³C NMR spectral data in the presence of paramagnetic lanthanides suggests conformational equilibria in the solutions. From the potentiometric studies, global formation constants have been determined, and speciation diagrams obtained over the pH range 1.5pH7.0 for ligand/metal ratios of 1 and 30. Implications of these results on lanthanide induced fusion of phospholipid membranes are discussed.     

Computationally-assisted approach to the vibrational spectra of molecular crystals: study of hydrogen-bonding and pseudo-polymorphism.

A new computationally-assisted methodology (PiMM), which accounts for the effects of intermolecular interactions in the crystal, is applied to the complete assignment of the Raman and infrared vibrational spectra of room temperature forms of crystalline caffeine, theobromine, and theophylline. The vibrational shifts due to crystal packing interactions are evaluated from ab initio calculations for a set of suitable molecular pairs, using the B3LYP/6-31G* approach.The proposed methodology provides an answer to the current demand for a reliable assignment of the vibrational spectra of these methyl-xanthines, and clarifies several misleading assignments. The most relevant intermolecular interactions in each system and their effect on the vibrational spectra are considered and discussed. Based on these results, significant insights are obtained for the structure of caffeine in the anhydrous form (stable at room temperature), for which no X-ray structure has been reported. A possible structure based on C((8))--H...N((9)) and C((1,3))--H...O intermolecular interactions is suggested.     

Development of a bionematicide with Paecilomyces lilacinus to control Meloidogyne incognita

Root-knot disease caused by Meloidogyne incognita is a matter of grave concern because it affects several economically important crop plants. The use of solid-state fermentation (SSF) may help to elaborate efficient formulations with fungi to be employed in the biologic control of nematodes. Attempts were made to select low-cost substrates for spore production of a strain of Paecilomyces lilacinus with known nematicide capacity. Coffee husks, cassava bagasse, and defatted soybean cake were utilized as substrates, and sugarcane bagasse was used as support. Fermentations were carried out in flasks covered with filter paper at 28°C for 10 d. The products obtained by SSF were evaluated for their nematicide activity in pot experiments containing one seedling of the plant Coleus inoculated with the nematode M. incognita. The plants were evaluated 2 mo after inoculation. Fermented products showed a reduction in the number of nematodes. The best results were obtained with defatted soybean cake, which showed almost 100% reduction in the number of nematodes; the reduction with coffee husk was 80% and with cassava bagasse was about 60%.     

The partial hydrogenation of benzene to cyclohexene by nanoscale ruthenium catalysts in imidazolium ionic liquids

The controlled decomposition of an Ru(0) organometallic precursor dispersed in 1-n-butyl-3-methylimidazolium hexafluorophosphate (BMI.PF(6)), tetrafluoroborate (BMI.BF(4)) or trifluoromethane sulfonate (BMI.CF(3)SO(3)) ionic liquids with H(2) represents a simple and efficient method for the generation of Ru(0) nanoparticles. TEM analysis of these nanoparticles shows the formation of superstructures with diameters of approximately 57 nm that contain dispersed Ru(0) nanoparticles with diameters of 2.6+/-0.4 nm. These nanoparticles dispersed in the ionic liquids are efficient multiphase catalysts for the hydrogenation of alkenes and benzene under mild reaction conditions (4 atm, 75 degrees C). The ternary diagram (benzene/cyclohexene/BMI.PF(6)) indicated a maximum of 1 % cyclohexene concentration in BMI.PF(6), which is attained with 4 % benzene in the ionic phase. This solubility difference in the ionic liquid can be used for the extraction of cyclohexene during benzene hydrogenation by Ru catalysts suspended in BMI.PF(6). Selectivities of up to 39 % in cyclohexene can be attained at very low benzene conversion. Although the maximum yield of 2 % in cyclohexene is too low for technical applications, it represents a rare example of partial hydrogenation of benzene by soluble transition-metal nanoparticles.     

Stereoselective conjugate addition of benzyl phenylsulfonyl carbanions to enoates derived from d-mannitol

The conjugate addition of benzylic phenylsulfonyl carbanions (2a'-d') to enoates derived from d-(+)-mannitol (E- or Z-1a-c) was studied using THF and THF/HMPA as solvent. Under kinetic conditions (-78 degrees C), enoate E-1a,b led to a mixture of syn-(R,S) and anti-(S,S) adducts (55/45), and syn-(R,S) adducts were the main product obtained ( approximately 90/10) from enoate Z-1a. Under thermodynamic conditions (-78 degrees C to room temperature) syn-(R,S) adducts were also preferentially formed ( approximately 90/10), despite the geometry at the double bond in the acceptor. Enoate 1c (E/Z = 57/43), bearing an additional benzyl group at the alpha-position, also reacted with carbanions 2'a,b, under thermodynamic conditions, leading to syn-adducts in excellent de (control at the three newly generated stereogenic centers). The adducts were quantitatively transformed into the corresponding beta-gamma-disubstituted gamma-butyrolactones and alpha,beta,gamma-trisubstituted gamma-butyrolactones. (1)H NMR studies (NOE and J-coupling) of these lactones allowed us to determine their configuration at the newly generated chiral centers. The reduction of the C-S bond in adducts syn-(R,S) with Na/Hg, followed by treatment of the resulting products in aqueous acid media, led to enantioenriched beta-benzyl-gamma-hydroxymethyl-gamma-butyrolactones. The conformational equilibrium of enoates E- and Z-1b was evaluated by theoretical calculations (ab initio, MP2/6-31G), and a mechanistic rationale was proposed to explain the observed stereoselectivities.     

Counterions in poly(allylamine hydrochloride) and poly(styrene sulfonate) layer-by-layer films

The amount of counterions in layer-by-layer (LBL) films of poly(allylamine hydrochloride) (PAH) and poly(styrene sulfonate) (PSS) has been determined with X-ray photoelectron spectroscopy (XPS) for films prepared from solutions with various NaCl concentrations. Sodium and chloride counterions are present in LBL films produced from salt solutions, which are located at the surface and in the bulk of the films. The percentage of bulk counterions increases with the ionic strength of the polyelectrolyte before reaching a constant value. The bulk sodium/sulfur percentage ratios tend to 0.8 for samples washed with pure water and for samples washed with NaCl aqueous solutions, while the bulk chlorine/nitrogen percentage ratios tend to 0.5 for the same samples. The ratio between the percentages of polyelectrolyte ionic groups lies close to unity for all samples, indicating that counterions do not contribute to charge compensation in the polyelectrolyte during the adsorption process. The presence of counterions in LBL films is explained by Manning condensation near the polyelectrolyte ionic groups, leading to inter-polyelectrolyte ionic bondings via ionic networks. It is believed that condensation leads to the formation of NaCl crystallites in these LBL films, which was confirmed by X-ray diffraction measurements.     

Methylation of Chitosan with Iodomethane: Effect of Reaction Conditions on Chemoselectivity and Degree of Substitution

N,N,N‐trimethylchitosan (TMC) was prepared by reacting purified chitosan with iodomethane, in the presence of sodium hydroxide, water and sodium iodide, at room temperature. The reaction medium was N‐methyl‐2‐pyrrolidone. Different samples of TMC were obtained by adding to the reaction medium a fixed volume (5.5 mL) of aqueous NaOH solutions at different concentrations (15, 20, 30 and 40 wt.‐%) and carrying out the reactions for 9 or 24 h. The features observed in the ¹H and ¹³C NMR spectra of these chitosan derivatives, in respect of the chemical shift, number and relative intensity of the signals, depended strongly on the excess of NaOH and H₃CI added to the reaction medium, but when the lowest excess was employed, the characteristics of the derivative were not affected by the reaction time to the same extent. The average degree of quaternization of these N‐methylated derivatives of chitosan ranged from 10.5% to 44.8%, according to the reaction conditions. Increasing the excess of NaOH, in reactions carried out for 9 h, resulted in TMC samples with progressively higher content of trimethylated sites however, the reaction yields were correspondingly lower and O‐alkylation was favored in these cases.

¹H NMR spectrum of sample [A_X]^24h dissolved in D₂O (C_p = 10 g/L).     

Structure and magnetism of VnBz(n+1) sandwich clusters

Results on structural, energetic, electronic, and magnetic properties of linear sandwich VnBzn+1 clusters obtained using high-accuracy density functional computations are presented and analyzed. Energetically close-lying configurations and states of different spin-multiplicities are identified. The computed characteristics are in good agreement with the available experimental data. The computations predict that the most stable forms of the clusters in the size range n >/= 4 are chiral. This feature, combined with the magnetism of these systems, makes them of potential importance as building blocks of nanosystems with coupled optical and magnetic functionalities.