Fundamental role of the fostriecin unsaturated lactone and implications for selective protein phosphatase inhibition

Key derivatives and analogues of fostriecin were prepared and examined that revealed a fundamental role for the unsaturated lactone and confirmed the essential nature of the phosphate monoester. Thus, an identical 200-fold reduction in protein phosphatase 2A (PP2A) inhibition is observed with either the saturated lactone (7) or with an analogue that lacks the entire lactone (15). This 200-fold increase in PP2A inhibition attributable to the unsaturated lactone potentially may be due to reversible C269 alkylation within the PP beta12-beta13 active site loop accounting for PP2A/4 potency and selectivity.     

Fluorocinnoline derivatives. II. Synthesis and antibacterial activity of fluorinated 1-alkyl-1,4-dihydro-4-oxocinnoline-3-carboxylic acids

Chemical modification of cinoxacin was studied with the aim of improving its antibacterial activity and spectrum. Alkylation of ethyl 6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnoline-3-carboxylates (1 and 7) with alkyl iodide or dialkyl sulfate gave ethyl 1-alkyl-6,7,8-trifluoro- and 6,7-difluoro-1,4-dihydro-4-oxocinnoline-3-carboxylates (2 and 8), together with the isomeric anhydro-bases 3 and 9 of 2-alkyl-3-ethoxycarbonyl-6,7,8-trifluoro- and 6,7-difluoro-4-hydroxycinnolinium hydroxides, respectively. Acid-catalyzed hydrolysis of the 1-alkyl derivatives 2 and 8 gave the corresponding carboxylic acids 4 and 10. The same treatment of 3 and 9, accompanied with decarboxylation of the inner salts 5 and 11, afforded the anhydro-bases 6 and 12 of 2-alkyl-4-hydroxycinnolinium hydroxides, respectively. Displacement reactions of 4 and 10 with nucleophiles such as amine, alkoxide and thiolate gave 7-substituted 1-alkyl-6,8-difluoro- and 6-fluoro-1,4-dihydro-4-oxocinnoline-3-carboxylic acids (13 and 17-35). Antibacterial activities of these compounds were evaluated and compared with those of cinoxacin and norfloxacin. Some compounds showed a broader spectrum and more potent activity than cinoxacin, but were considerably inferior in activity to norfloxacin.     

The regioselectivity of the formation of 2-pyrazolylthiazoles and their precursors from the reaction of 2-hydrazinothiazoles with 4,4,4-trifluoro-1-hetaryl-1,3-butanediones

Reaction of 2-hydrazinothiazoles 1 with 1-thienyl- and 1-furyl-1,3-butanediones 2a,b in methanol in the presence of hydrochloric acid mainly leads to a mixture of pyrazoles 3 and pyrazolines 4 or pyrazoles 3 and 5 in strong acidic conditions. Isomeric hydrazones 6 and pyrazolines 4 were formed and isolated in these reactions in the absence of hydrochloric acid. It has been shown that the regioselectivity in the reaction of diketones 2 with hydrazine 1 is governed by both the concentration of acid and the nature of substituents in the 1,3-diketones 2. Cyclization of hydrazones 6 is shown to occur under milder conditions than dehydration for pyrazolines 4. The new heterocyclic compounds were prepared and fully characterized by NMR spectra and by X-ray analysis for 3c.     

Pressure effects on the phase transition of urea adducts withn-paraffins and polyethylene

The decomposition of urea adducts with hydrocarbons is treated as a first-order phase transition and the pressure dependence is studied up to 0.7 GPa for several kinds of adducts. The thermodynamic quantities at the decomposition of the adduct can be analysed as a sum of those quantities of the component materials. The transition from the orthorhombic to the hexagonal form of the adduct with polyethylene is also investigated by X-ray diffraction and the pressure dependence of the lattice parameters is measured for the adducts. The results are compared with the phase transition in the pure paraffin.     

Synthesis of glutamate by reductive amination of 2-oxoglutarate with the combination of hydrogenase and glutamate dehydrogenase

Glutamate synthesis by reductive amination of 2-oxoglutarate was performed by the combination of NADH regeneration system and glutamate dehydrogenase (GluDH). The conversion of 2-oxoglutamate to glutamate was 98% after 3 h, and the turnover number of NAD⁺was 17.     

Synthesis of some isomeric 4,11-dihydro-5H-[1]benzoxocino[4,3-d] or [3,4-c]isoxazol-5-ones and isomeric 4,5,10,11-tetrahydrobenzo[5,6]-cycloocta[2,1-d] or [1,2-c]isoxazol-5-ones

The title compounds were prepared by acid-catalyzed cyclization of aryloxymethyl- or (2-arylethyl)-4-carboxymethylisoxazoles which in turn were synthesized from aryloxymethyl- or (2-arylethyl)isoxazole-4-carboxylic acids by Arndt-Eistert homologation.     

Chemical reaction dynamics of PeCB and TCDD decomposition: A tight‐binding quantum chemical molecular dynamics study with first‐principles parameterization

The decomposition reaction dynamics of 2,3,4,4′,5‐penta‐chlorinated biphenyl (2,3,4,4′,5‐PeCB), 3,3′,4,4′,5‐penta‐chlorinated biphenyl (3,3′,4,4′,5‐PeCB), and 2,3,7,8‐tetra‐chlorinated dibenzo‐p‐dioxin (2,3,7,8‐TCDD) was clarified for the first time at atomic and electronic levels, using our novel tight‐binding quantum chemical molecular dynamics method with first‐principles parameterization. The calculation speed of our new method is over 5000 times faster than that of the conventional first‐principles molecular dynamics method. We confirmed that the structure, energy, and electronic states of the above molecules calculated by our new method are quantitatively consistent with those by first‐principles calculations. After the confirmation of our methodology, we investigated the decomposition reaction dynamics of the above molecules and the calculated dynamic behaviors indicate that the oxidation of the 2,3,4,4′,5‐PeCB, 3,3′,4,4′,5‐PeCB, and 2,3,7,8‐TCDD proceeds through an epoxide intermediate, which is in good agreement with the previous experimental reports and consistent with our static density functional theory calculations. These results proved that our new tight‐binding quantum chemical molecular dynamics method with first‐principles parameterization is an effective tool to clarify the chemical reaction dynamics at reaction temperatures. © 2004 Wiley Periodicals, Inc. Int J Quantum Chem, 2005     

Vapor Pressure and Solid Phases of Methanol below Its Triple Point Temperature

We present an experimental work devoted to study of the thermodynamical properties of solid methanol. We combine Fourier transform infrared spectroscopy (FTIR) and mass spectrometry (MS) to measure, for the first time, the vapor pressure of various methanol solid phases and determine their Clausius-Clapeyron equations. We perform our experiments between T = 130 K and the triple point temperature T(t) = 175.61 K. When methanol is condensed from its vapor below T(t), we observe three different solid phases depending on temperature. A condensation at T = 130 K forms a metastable phase with an enthalpy of sublimation deltaH(metastable-vapor) = 42.9 +/- 0.5 kJ.mol(-1). Upon heating, this phase transforms itself at T approximately 145 K to the alpha-phase that has an enthalpy of sublimation deltaH(alpha-vapor) = 46.9 +/- 0.2 kJ.mol(-1). Cooling the alpha-phase does not lead back to the metastable phase, whereas heating this alpha-phase leads to the beta-phase occurrence at T(alpha-beta) = 157.36 K. This latter one is stable until T(t) and has an enthalpy of sublimation deltaH(beta-vapor) = 44.2 +/- 0.5 kJ.mol(-1).