Ruthenium carbene complexes with N,N'-bis(mesityl)imidazol-2-ylidene ligands: RCM catalysts of extended scope

The ruthenium carbene complexes 3a,b bearing imidazol-2-ylidene ligands constitute excellent precatalysts for ring-closing metathesis (RCM) reactions allowing the formation of tri- and tetrasubstituted cycloalkenes. They also apply to annulations that are beyond the scope of the standard Grubbs carbene 1 as well as to ring-closing reactions of acrylic acid derivatives even if the resulting alpha,beta-unsaturated lactones (or lactams) are tri- or tetrasubstituted. The reactivity of 3a was found to be highly dependent on the reaction medium: particularly high reaction rates are observed in toluene, although this solvent also leads to an increased tendency of the catalyst to isomerize the double bonds of the substrates.     

Weakly coordinating anions HA2-generated from oxoanions A- and their conjugate acids. Coordination equilibria,ionic conductivities,and the structures of [Cu2(H(CH3SO3)2)4]n and [Cu(CO)(H(CF3CO2)2)]2

The coordination or ion pairing of the hydrogen-bonded anions H(CF3CO2)2- and H(CH3SO3)2- to NEt4+, Li+, Cu+, and/or Cu2+ was investigated. The structure of [Cu2(H(CH3SO3)2)4]n consists of centrosymmetric dimeric moieties that contain two homoconjugated (CH3SO2O-H...OSO2CH3)- anions per Cu2+ ion, forming typical Jahn-Teller tetragonally elongated CuO6 coordination spheres. The oxygen atoms involved in the nearly linear O-H...O hydrogen bonds (O...O approximately 2.62 A) are not coordinated to the Cu2+ ions. The structure of Cu2(CO)2(H(CF3-CO2)2)2 consists of pseudo-C2-symmetric dimers that contain one homoconjugated (CF3COO-H...OCOCF3)- anion per Cu+ ion, forming highly distorted tetrahedral Cu(CO)O3 coordination spheres. Three of the four oxygen atoms in each hydrogen-bonded H(CF3CO2)2- anion are coordinated to the Cu+ ions, including one of the oxygen atoms in each O-H...O hydrogen bond (O...O approximately 2.62 A). Infrared spectra (v(CO) values) of Cu(CO)(CF3CO2) or Cu(CO)(CH3SO3) dissolved in acetonitrile or benzene, with and without added CF3COOH or CH3SO3H, respectively, demonstrate that HA2- anions involving carboxylates or sulfonates are more weakly coordinating than the parent anions RCO2- and RSO3-. Direct current conductivities of THF solutions of Li(CF3CO2) containing varying concentrations of added CF3COOH further demonstrate that Li+ and NEt4+ ion pair much more weakly with H(CF3CO2)2- than with CF3CO2-.     

Synthesis and structure of a heptanuclear nickel(II) complex uniquely exhibiting four distinct binding modes,two of which are novel,for a hydroxamate ligand

The reaction of 2-(dimethylamino)phenylhydroxamic acid (2-dmAphaH) with NiSO(4).6H2O gives the complex [Ni7(2-dmAphaH-1)2(2-dmApha)8(H2O)2]SO(4).15H2O uniquely exhibiting four distinct hydroxamate binding modes, two of which are novel, and showing both antiferromagnetic and ferromagnetic interactions in contrast to [Cu5(2-dmAphaH-1)4(HSO4)2(MeOH)2].2MeOH, a strongly antiferromagnetic metallacrown formed with CuSO(4).5H2O.     

Structure, stereochemistry, and biological activity of integramycin, a novel hexacyclic natural product produced by Actinoplanes sp. that inhibits HIV-1 integrase

[structure: see text] HIV-1 integrase is a critical enzyme for viral replication, and its inhibition is an emerging target for potential antiviral chemotherapy. We have discovered a novel inhibitor, integramycin, from screening of fermentation extracts using an in vitro assay. Integramycin possesses a hexacyclic ring system and exhibited an IC50 value of 4 microM against HIV-1 integrase (strand transfer). The isolation, structure elucidation, stereochemistry, conformation, and biological activity has been described.     

Quantification of clenbuterol in equine plasma,urine and tissue by liquid chromatography coupled on-line with quadrupole time-of-flight mass spectrometry

Clenbuterol (CBL) is a potent beta(2)-adrenoceptor agonist used for the management of respiratory disorders in the horse. The detection and quantification of CBL can pose a problem due to its potency, the relatively low dose administered to the horse, its slow clearance and low plasma concentrations. Thus, a sensitive method for the quantification and confirmation of CBL in racehorses is required to study its distribution and elimination. A sensitive and fast method was developed for quantification and confirmation of the presence of CBL in equine plasma, urine and tissue samples. The method involved liquid-liquid extraction (LLE), separation by liquid chromatography (LC) on a short cyano column, and pseudo multiple reaction monitoring (pseudo-MRM) by electrospray ionization quadrupole time-of-flight tandem mass spectrometry (ESI-QTOF-MS/MS). At very low concentrations (picograms of CBL/mL), LLE produced better extraction efficiency and calibration curves than solid-phase extraction (SPE). The operating parameters for electrospray QTOF and yield of the product ion in MRM were optimized to enhance sensitivity for the detection and quantification of CBL. The quantification range of the method was 0.013-10 ng of CBL/mL plasma, 0.05-20 ng/0.1 mL of urine, and 0.025-10 ng/g tissue. The detection limit of the method was 13 pg/mL of plasma, 50 pg/0.1 mL of urine, and 25 pg/g of tissue. The method was successfully applied to the analysis of CBL in plasma, urine and various tissue samples, and in pharmacokinetic (PK) studies of CBL in the horse. CBL was quantified for 96 h in plasma and 288 h in urine post-administration of CLB (1.6 micro g/kg, 2 x daily x 7 days). This method is useful for the detection and quantification of very low concentrations of CBL in urine, plasma and tissue samples.     

Libraries of composite polyfluors built from fluorescent deoxyribosides

We report on a new class of water-soluble fluorescent molecules (polyfluors) that are composed of multiple individual fluorophores assembled on a DNA-like backbone. Four fluorophore deoxyribosides were synthesized, and these individual molecules were assembled into oligofluor strings on a DNA synthesizer. A library of 256 tetrafluors was generated by split and pool methods on polystyrene beads. Images of the library under a fluorescence microscope revealed at least 40-50 different hues and intensities. Selected tetrafluors were resynthesized in pure form in solution and displayed properties, such as large Stokes shifts, that individual fluorophores do not have.     

Surface activity of thymol: implications for an eventual pharmacological activity

In the present work, we studied the ability of thymol to affect the organization of model membranes and the activity of an intrinsic membrane protein, the GABA(A) receptor (GABA(A)-R). In this last aspect, we tried to elucidate if the action mechanism of this terpene at the molecular level, involves its binding to the receptor protein, changes in the organization of the receptor molecular environment, or both. The self-aggregation of thymol in water with a critical micellar concentration approximately = 4 microM and its ability to penetrate in monomolecular layers of soybean phosphatidylcholine (sPC) at the air-water interface, even at surface pressures above the equilibrium, lateral pressure of natural bilayers were demonstrated. Thymol affected the self-aggregation of Triton X-100 and the topology of sPC vesicles. It also increased the polarity of the membrane environment sensed by the electrochromic dye merocyanine. A dipolar moment of 1.341 Debye was calculated from its energy-minimized structure. Its effect on the binding of [3H]-flunitrazepam ([3H]-FNZ) to chick brain synaptosomal membranes changed qualitatively from a tendency to the inhibition to a clear activatory regime, up on changing the phase state of the terpene (from a monomeric to a self-aggregated state). Above its CMC, thymol increased the affinity of the binding of [3H]-FNZ (K(d-control)= 2.9, K(d-thymol)= 1.7 nM) without changing the receptor density (B(max-control)= 910, B(max-thymol)= 895 fmol/mg protein). The activatory effect of thymol on the binding of [ [3H]-FNZ was observed even in the presence of the allosteric activator gamma-aminobutyric acid (GABA) at a concentration of maximal activity, and was blocked by the GABA antagonist bicuculline. Changes in the dipolar arrangement and in the molecular packing of GABA(A)-R environment are discussed as possible mediators of the action mechanism of thymol.     

Insights into the Decomposition of Olefin Metathesis Precatalysts

The decomposition of a series of benzylidene, methylidene, and 3‐phenylindenylidene complexes has been probed in alcohol solution in the presence of base. Tricyclohexylphosphane‐containing precatalysts are shown to yield [RuCl(H)(H₂)(PCy₃)₂] in isopropyl alcohol solutions, while 3‐phenylindenylidene complexes lead to η⁵‐(3‐phenyl)indenyl products. The potential‐energy surfaces for the formation of the latter species have been probed using density functional theory studies.     

A Tandem In Situ Peptide Cyclization through Trifluoroacetic Acid Cleavage

We present a new approach for peptide cyclization during solid phase synthesis under highly acidic conditions. Our approach involves simultaneous in situ deprotection, cyclization and trifluoroacetic acid (TFA) cleavage of the peptide, which is achieved by forming an amide bond between a lysine side chain and a succinic acid linker at the peptide N‐terminus. The reaction proceeds via a highly active succinimide intermediate, which was isolated and characterized. The structure of a model cyclic peptide was solved by NMR spectroscopy. Theoretical calculations support the proposed mechanism of cyclization. Our new methodology is applicable for the formation of macrocycles in solid‐phase synthesis of peptides and organic molecules.