Molar extinction coefficients of some carbohydrates in aqueous solutions

Molar extinction coefficients of some carbohydrates viz. l-arabinose (C₅H₁₀O₅), d-glucose (C₆H₁₂O₆), d-mannose (C₆H₁₂O₆), d-galactose (C₆H₁₂O₆), d(-) fructose (C₆H₁₂O₆) and maltose (C₁₂H₂₄O₁₂) in aqueous solutions have been determined at 81, 356, 511, 662, 1173 and 1332 keV by gamma ray transmission method in a narrow beam good geometry set-up. These coefficients have been found to depend upon the photon energy following a 4-parameter polynomial. These extinction coefficients for different sugars having the same molecular formula have same values varying within experimental uncertainty. Within concentration ranges studied, Beer-Lambert law is obeyed very well.     

Discovery of potent and specific fructose-1,6-bisphosphatase inhibitors and a series of orally-bioavailable phosphoramidase-sensitive prodrugs for the treatment of type 2 diabetes

Excessive glucose production by the liver coupled with decreased glucose uptake and metabolism by muscle, fat, and liver results in chronically elevated blood glucose levels in patients with type 2 diabetes. Efforts to treat diabetes by reducing glucose production have largely focused on the gluconeogenesis pathway and rate-limiting enzymes within this pathway such as fructose-1,6-bisphosphatase (FBPase). The first potent FBPase inhibitors were identified using a structure-guided drug design strategy (Erion, M. D.; et al. J. Am. Chem. Soc. 2007, 129, 15480-15490) but proved difficult to deliver orally. Herein, we report the synthesis and characterization of a series of orally bioavailable FBPase inhibitors identified following the combined discoveries of a low molecular weight inhibitor series with increased potency and a phosphonate prodrug class suitable for their oral delivery. The lead inhibitor, 10A, was designed with the aid of X-ray crystallography and molecular modeling to bind to the allosteric AMP binding site of FBPase. High potency (IC50 = 16 nM) and FBPase specificity were achieved by linking a 2-aminothiazole with a phosphonic acid. Free-energy perturbation calculations provided insight into the factors that contributed to the high binding affinity. 10A and standard phosphonate prodrugs of 10A exhibited poor oral bioavailability (0.2-11%). Improved oral bioavailability (22-47%) was achieved using phosphonate diamides that convert to the corresponding phosphonic acid by sequential action of an esterase and a phosphoramidase. Oral administration of the lead prodrug, MB06322 (30, CS-917), to Zucker Diabetic Fatty rats led to dose-dependent inhibition of gluconeogenesis and endogenous glucose production and consequently to significant blood glucose reduction.     

Studies of iron(II) and iron(III) complexes with fac-N2O, cis-N2O2 and N2O3 donor ligands: models for the 2-His 1-carboxylate motif of non-heme iron monooxygenases

Enzymes in the oxygen-activating class of mononuclear non-heme iron oxygenases (MNOs) contain a highly conserved iron center facially ligated by two histidine nitrogen atoms and one carboxylate oxygen atom that leave one face of the metal center (three binding sites) open for coordination to cofactor, substrate, and/or dioxygen. A comparative family of [Fe(II/III)(N(2)O(n))(L)(4-n))](±x), n = 1-3, L = solvent or Cl(-), model complexes, based on a ligand series that supports a facially ligated N,N,O core that is then modified to contain either one or two additional carboxylate chelate arms, has been structurally and spectroscopically characterized. EPR studies demonstrate that the high-spin d(5) Fe(III)g = 4.3 signal becomes more symmetrical as the number of carboxylate ligands decreases across the series Fe(N(2)O(3)), Fe(N(2)O(2)), and Fe(N(2)O(1)), reflecting an increase in the E/D strain of these complexes as the number of exchangeable/solvent coordination sites increases, paralleling the enhanced distribution of electronic structures that contribute to the spectral line shape. The observed systematic variations in the Fe(II)-Fe(III) oxidation-reduction potentials illustrate the fundamental influence of differential carboxylate ligation. The trend towards lower reduction potential for the iron center across the [Fe(III)(N(2)O(1))Cl(3)](-), [Fe(III)(N(2)O(2))Cl(2)](-) and [Fe(III)(N(2)O(3))Cl](-) series is consistent with replacement of the chloride anions with the more strongly donating anionic O-donor carboxylate ligands that are expected to stabilize the oxidized ferric state. This electrochemical trend parallels the observed dioxygen sensitivity of the three ferrous complexes (Fe(II)(N(2)O(1)) < Fe(II)(N(2)O(2)) < Fe(II)(N(2)O(3))), which form μ-oxo bridged ferric species upon exposure to air or oxygen atom donor (OAD) molecules. The observed oxygen sensitivity is particularly interesting and discussed in the context of α-ketoglutarate-dependent MNO enzyme mechanisms.     

Preparation of 8-(arylsulfanyl)adenines with diazonium salts under mild, aerobic conditions

8-(Arylsulfanyl)adenines 11 were prepared in up to 75% yield by reacting the 8-thionoadenine 6 (acetic acid 3-(6-amino-8-thioxo-7,8-dihydropurin-9-yl)propyl ester) with benzenediazonium tetrafluoroborates in DMSO. Benzenediazonium ions carrying an electron-withdrawing substituent gave the highest yields. The reaction proceeded smoothly at room temperature without any base and could be performed under air atmosphere. The extremely mild conditions are compatible with a wide range of functional groups.     

Dichlorocarbene Addition to

In contrast to the terminal phosphinidene complex PhPW(CO)(5) (2), which adds to [5]metacyclophane (1) in a 1,4-fashion, dichlorocarbene preferentially adds in a 1,2-fashion to the formal "anti-Bredt" type double bond of the aromatic ring of 1 to afford the norcaradiene 11b, which immediately rearranges to the bridged cycloheptatriene 12b and further by a [1,5] sigmatropic chlorine migration to the isomeric 13b as the first observable product. More slowly, the latter isomerizes via a dissociative mechanism to give 15b. A computational study supports the notion that the [1,5] chlorine migration in the rearrangement 12b --> 13b, for which an activation barrier of 70.2 kJ mol(-)(1) was calculated, is essentially concerted with minor charge separation. In contrast, the analogous [1,5] chlorine migration in the flat model compound 7,7-dichlorocycloheptatriene (12a) displays features of a dissociative pathway.     

Spatially varying SAR models and Bayesian inference for high-resolution lattice data

We discuss a new class of spatially varying, simultaneous autoregressive (SVSAR) models motivated by interests in flexible, non-stationary spatial modelling scalable to higher dimensions. SVSAR models are hierarchical Markov random fields extending traditional SAR models. We develop Bayesian analysis using Markov chain Monte Carlo methods of SVSAR models, with extensions to spatio-temporal contexts to address problems of data assimilation in computer models. A motivating application in atmospheric science concerns global CO emissions where prediction from computer models is assessed and refined based on high-resolution global satellite imagery data. Application to synthetic and real CO data sets demonstrates the potential of SVSAR models in flexibly representing inhomogeneous spatial processes on lattices, and their ability to improve estimation and prediction of spatial fields. The SVSAR approach is computationally attractive in even very large problems; computational efficiencies are enabled by exploiting sparsity of high-dimensional precision matrices.     

Thermodynamics of Chromium(VI) Anionic Species Sorption onto Surfactant-Modified Montmorillonite Clay

Batch sorption experiments performed on Cr(VI) species sorption showed a significantly enhanced removal of inorganic hexavalent chromium anionic species from aqueous solution by montmorillonite clays modified with quaternary amine, hexadecyltrimethylammonium (HDTMA) bromide. Unmodified clay had no affinity for chromium(VI) species. The sorption of Cr(VI) species has been carried out as a function of pH, contact time, adsorbate concentration (4.14x10(-5) to 8.62x10(-3) M), and temperature (5-45 degrees C). The surfactant-modified clay surface was stable when exposed to extremes in pH. The optimum pH for maximum sorption of Cr(VI) species was found to be at pH 1 and was constant between pH 2 and pH 6. The sorption data obtained was well described by DKR and Langmuir sorption isotherms. Sorption energy (E) for (i) surfactant sorption by montmorillonite clay and (ii) sorption of chromium(VI) species by surfactant modified clay have been computed from the DKR equation. Sorption energy evaluated for the sorption of both surfactant and Cr(VI) species showed that an ion-exchange mechanism was operative. The mechanism of retention appears to be replacement of counterion of the surfactant by Cr(VI) anionic species. Adsorbent capacity for the sorption of Cr(VI) species has been evaluated from the Langmuir sorption isotherm data. Thermodynamic parameters (Delta H degrees, Delta S degrees and Delta G degrees ) for surfactant sorption on montmorillonite clay and Cr(VI) sorption by modified clay have been evaluated. The specific rate constant for sorption of Cr(VI) species on modified montmorillonite was rapid during the first 10 min and equilibrium was found to be attained within 30 min. The sorption of Cr(VI) species onto modified montmorillonite clay followed first-order rate kinetics. Copyright 2000 Academic Press.