Pharmacokinetic properties of N‐nitrosofenfluramine after its administration to rats

N‐Nitrosofenfluramine (N‐Fen), a synthetic adulterant in Chinese herbal diet products, is believed to cause hepatotoxicity in people who use these products. N‐Fen is a relatively new compound, and thus pharmacological and toxicological studies are insufficient. The aim of this work was to (1) define N‐Fen's plasma pharmacokinetics and tissue distribution after single intraperitoneal (i.p.) administration of 25 mg/kg to rats; (2) define its bioavailability; and (3) identify fenfluramine (Fen) and norfenfluramine (Norf) as N‐Fen metabolites. N‐Fen rapidly appeared in the circulation and was distributed to all tissues. Norf was found to be the primary metabolite and not Fen. Plasma and tissue levels of N‐Fen and Norf were low with bioavailability of N‐Fen after i.p. administration was <3%. The AUC_0−t of N‐Fen in the liver and kidney were 6.6 and 12.1 times, respectively, greater than the brain, and 17.8 and 32.6 times, respectively, greater than the plasma. In conclusion, N‐Fen did not show local accumulation in the liver, the site of toxicity, with concentrations represented as percentage of the total dose ranginng from 0.008 to 0.122%; hence the cause of hepatotoxicity could be related to the mechanisms other than toxicity consequences accumulation. Copyright © 2010 John Wiley & Sons, Ltd.     

Probing the transition from hydrophilic to hydrophobic solvation with atomic scale resolution

Picosecond and femtosecond X-ray absorption spectroscopy is used to probe the changes of the solvent shell structure upon electron abstraction of aqueous iodide using an ultrashort laser pulse. The transient L(1,3) edge EXAFS at 50 ps time delay points to the formation of an expanded water cavity around the iodine atom, in good agreement with classical and quantum mechanical/molecular mechanics (QM/MM) molecular dynamics (MD) simulations. These also show that while the hydrogen atoms pointed toward iodide, they predominantly point toward the bulk solvent in the case of iodine, suggesting a hydrophobic behavior. This is further confirmed by quantum chemical (QC) calculations of I(-)/I(0)(H(2)O)(n=1-4) clusters. The L(1) edge sub-picosecond spectra point to the existence of a transient species that is not present at 50 ps. The QC calculations and the QM/MM MD simulations identify this transient species as an I(0)(OH(2)) complex inside the cavity. The simulations show that upon electron abstraction most of the water molecules move away from iodine, while one comes closer to form the complex that lives for 3-4 ps. This time is governed by the reorganization of the main solvation shell, basically the time it takes for the water molecules to reform an H-bond network. Only then is the interaction with the solvation shell strong enough to pull the water molecule of the complex toward the bulk solvent. Overall, much of the behavior at early times is determined by the reorientational dynamics of water molecules and the formation of a complete network of hydrogen bonded molecules in the first solvation shell.     

A synergistic approach to polycyclics via a strategic utilization of Claisen rearrangement and olefin metathesis

Olefin metathesis promoted by a well-defined metal carbene complex has evolved into an efficient method for the construction of a broad range of carbocyclic and heterocyclic rings of varying size. The synthetic potential of the olefin metathesis has been further increased by combining various other C-C bond forming processes either in tandem or in sequence. Herein, application of Claisen rearrangement and olefin metathesis to prepare various intricate and/or biologically important targets has been described.     

Docking-based comparative intermolecular contacts analysis as new 3-D QSAR concept for validating docking studies and in silico screening: NMT and GP inhibitors as case studies

The significant role played by docking algorithms in drug discovery combined with their serious pitfalls prompted us to envisage a novel concept for validating docking solutions, namely, docking-based comparative intermolecular contacts analysis (dbCICA). This novel approach is based on the number and quality of contacts between docked ligands and amino acid residues within the binding pocket. It assesses a particular docking configuration on the basis of its ability to align a set of ligands within a corresponding binding pocket in such a way that potent ligands come into contact with binding site spots distinct from those approached by low-affinity ligands and vice versa. In other words, dbCICA evaluates the consistency of docking by assessing the correlation between ligands' affinities and their contacts with binding site spots. Optimal dbCICA models can be translated into valid pharmacophore models that can be used as 3-D search queries to mine structural databases for new bioactive compounds. dbCICA was implemented to search for new inhibitors of candida N-myristoyl transferase as potential antifungal agents and glycogen phosphorylase (GP) inhibitors as potential antidiabetic agents. The process culminated in five selective micromolar antifungal leads and nine GP inhibitory leads.     

Chemical and nanomechanical analysis of rice husk modified by ATRP-grafted oligomer

Rice husk (RH), an abundant agricultural residue, was reacted with 2-bromoisobutyryl bromide, to convert it to a heterogeneous polyfunctional macroinitiator for Atom Transfer Radical Polymerization (ATRP). The number of active sites placed on the RH surface was small, but they were ATRP active. Non-polar methyl methacrylate (MMA) and polar acrylonitrile (AN) were polymerized from the RH, and a sequential monomer addition was used to prepare an amphiphilic PMMA-b-PAN copolymer on RH surface. FTIR qualitatively confirmed the grafting. Gravimetric and XPS analysis of the different RH surface compositions indicated thin layers of oligomeric PMMA, PAN, and PMMA-b-PAN. The modified surfaces were mapped by nanomechanical AFM to measure surface roughness, and adhesion and moduli using the Derjaguin-Muller-Toropov model. RH grafted with MMA possessed a roughness value of 7.92, and a hard and weakly adhering surface (13.1 GPa and 16.7 nN respectively) while RH grafted with AN yielded a roughness value of 29 with hardness and adhesion values of 4.0 GPa and 23.5 nN. The PMMA-b-PAN modification afforded a surface with a roughness value of 51.5 nm, with hardness and adhesion values of 3.0 GPa and 75.3 nN.     

Spectroscopic study of (two-dimensional) molecule-based magnets: [M(II)(TCNE)(NCMe)2][SbF6] (M = Fe, Mn, Ni)

The M-[TCNE] (M = 3d metal; TCNE = tetracyanoethylene) system is one of the most interesting classes of molecule-based magnets, exhibiting a plethora of compositions and structures (inorganic polymer chains, 2D layers, 3D networks, and amorphous solids) with a wide range of magnetic ordering temperatures (up to 400 K). A systematic study of vibrational (both infrared and, for the first time, Raman) properties of the family of new TCNE-based magnets of M(II)(TCNE) (NCMe)(2)[SbF(6)] [M = Mn, Fe, Ni] composition is discussed in conjunction with their magnetic behavior and newly reso-lved crystal structures. The vibrational properties of the isolated TCNE(●-) anion in the paramagnetic Bu(4)N [TCNE(●-)] salt and recently characterized 2D layered magnet Fe(II)(TCNE)(NCMe)(2)[FeCl(4)] are also reported for comparison. Additionally, a linear correlation between ν(C=C) (a(g)) frequency of the TCNE ligand and its formal charge Z (the spin density on the π* orbital), Z = [1571 - ν(C=C) (a(g))]/154.5 [e], is presented. It is shown that monitoring Z by Raman spectroscopy is of great use in providing information that allows understanding the peculiarity of the superexchange interaction in M-[TCNE] magnets and establishing the structure-magnetic properties correlations in this class of magnetic material.     

Receptor design and extraction of inorganic fluoride ion from aqueous medium

A receptor with acidic methylene hydrogens is found to act as an efficient binding mode for F(-). This reagent could as well be used for selective and quantitative extraction of F(-) from the aqueous solution of NaF and sea water.     

A three-way synergy of triple-modified Bi2WO6/Ag/N-TiO2 nanojunction film for enhanced photogenerated charges utilization

We demonstrate a general strategy to prepare Bi(2)WO(6)/Ag/N-TiO(2) film with double visible-light-active components bridged by Ag nanoparticles as an electron shuttle, which exhibits enhanced photocatalytic activity and photoelectrochemical performance under visible light.     

UV-Vis, fluorescence and NMR spectroscopic investigations on inclusion properties of a designed tetrahomocalix[8]arene with fullerenes C60 and C70 in solution

The present article reports the spectroscopic investigations on non-covalent interaction of fullerenes C(60) and C(70) with a macrocyclic receptor molecule, namely, 1,3,5,7-tetrahomo-p-tert-butylcalix[8]arene (1) in toluene. Jobs method of continuous variation reveals 1:1 stoichiometry for the fullerene complexes of 1. The most fascinating feature of the present study is that 1 binds selectively C(60) compared to C(70) as obtained from binding constant (K) data of C(60)-1 (K(C60-1)) and C(70)-1 (K(C70-1)) complexes which are enumerated to be 265,000 dm(3) mol(-1) and 63,43 dm(3) mol(-1), respectively, and selectivity in binding (K(C60-1)/K(C70-1)) is estimated to be 4.18 as obtained from UV-Vis study. Steady state fluorescence studies reveal quenching of fluorescence of 1 in presence of fullerenes and the K value of the C(60)-1 and C(70)-1 complexes are estimated to be 80,760 and 68,780 dm(3) mol(-1), respectively, with selectivity in binding (K(C60-1)/K(C70-1)) ~1.18. (1)H NMR analysis provides very good support in favor of strong binding between C(60) and 1. The high value of K value for C(60)-1 complex indicates that 1 forms an inclusion complex with C(60).