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Context: Serotonin toxicity is a reported complication associated with both therapeutic use and overdose of metaxalone while on therapeutic doses of serotonergic drugs such as serotonin reuptake inhibitors. Monoamine oxidase A (MAO-A) inhibition by metaxalone has been proposed as the etiology of this toxicity. Metaxalone concentrations reported with cases of serotonin toxicity range from 31 to 61 mcg/ml (140-276 µM). We investigated the effect of metaxalone on MAO-A activity using an in vitro model.Methods: Metaxalone at concentrations ranging from 1.56 to 400 µM were incubated with a proprietary MAO substrate and recombinant human MAO-A for 1 h. After that, an esterase and luciferase were added and luminescence measured. Clorgyline, a known MAO-A inhibitor, was used as a positive control. Luminescence was measured using a Biotek Synergy HT microplate reader.Results: Metaxalone demonstrated significant dose-related inhibition of MAO-A activity. Four-parameter logistic regression analysis demonstrated a strong dose-response relationship at increasing concentrations.Conclusions: Our in vitro model shows that at toxic concentrations similar to those reported in case reports metaxalone shows significant MAO-A inhibition. Clinicians should be aware of this mechanism and understand the potentially lethal interactions metaxalone can have when prescribed with other serotonergic drugs and consider this as a potential cause of serotonin toxicity, especially in overdose scenarios.

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INTRODUCTION: Whole bowel irrigation (WBI) is a management option for overdose of medications poorly adsorbed to activated charcoal, with modified release properties, or for body packers. Polyethylene glycol (PEG) is a mixture of ethylene oxide polymers of varying molecular weight. PEG with an average molecular weight of 3350 g/mol is used for WBI. PEG electrolyte lavage solution has been shown in vitro to hasten the dissolution of acetaminophen. The impact of PEG on the pharmacokinetics of extended release pharmaceuticals is unknown. Lower average molecular weight PEG mixtures are used as solvents and excipients. We sought to investigate the impact of PEG on the release of morphine from several extended release morphine formulations. METHODS: An in vitro gastric model was developed. To test the validity of our model, we first investigated the previously described interaction of ethanol and Avinza®. Once demonstrated, we then investigated the effect of PEG with several extended release morphine formulations. RESULTS: In the validation portion of our study, we confirmed an ethanol Avinza® interaction. Subsequently, we did not observe accelerated release of morphine from Avinza® or generic extended release morphine in the presence of PEG. CONCLUSION: The use of PEG for gastric decontamination following ingestion of these extended release morphine formulations is unlikely to accelerate morphine release and aggravate intoxication.

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The title compound, C35H53NO5·CH3OH {systematic name: (3S,6E,8S,9R,10E,12S,13S,14E,16S,17R)-3-benzyl-9,13-dihy-droxy-6,8,10,12,14,16-hexa-methyl-17-[(2S,4S)-4-methyl-hexan-2-yl]-1-oxa-4-aza-cyclo-hepta-deca-6,10,14-triene-2,5-dione methanol-d 4 monosolvate}, was extracted from conidia of the fungus Metarhizium acridum. Crystals were obtained as a methanol-d 4 solvate. The tail part of the 4-methyl-hexan-2-yl group exhibits disorder over two positions, with an occupancy ratio of 0.682 (9):0.318 (9). The crystal structure confirms the absolute configuration of nine stereocenters determined previously for the acetyl-ated compound metacridamide A. In the crystal, the methanol-d4 mol-ecule is positioned close to the O atom in the carbonyl group of the peptide bond, forming an O-H⋯O hydrogen bond. It also forms an O-H⋯O hydrogen bond with an adjacent mol-ecule. N-H⋯O and O-H⋯O hydrogen bonds are observed between neighboring mol-ecules.

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Metarhizium acridum, an entomopathogenic fungus, has been commercialized and used successfully for biocontrol of grasshopper pests in Africa and Australia. Its conidia produce two novel 17-membered macrocycles, metacridamides A and B, which consist of a Phe unit condensed with a nonaketide. Planar structures were elucidated by a combination of mass spectrometric and NMR techniques. Following hydrolysis of 1, chiral amino acid analysis assigned the L-configuration to the Phe unit. A crystal structure established the absolute configuration of the eight remaining stereogenic centers in 1. Metacridamide A showed cytotoxicity to three cancer lines with IC50's of 6.2, 11.0, and 10.8 µM against Caco-2 (epithelial colorectal adenocarcinoma), MCF-7 (breast cancer), and HepG2/C3A (hepatoma) cell lines, respectively. In addition, metacridamide B had an IC50 of 18.2 µM against HepG2/C3A, although it was inactive at 100 µM against Caco-2 and MCF-7. Neither analogue showed antimicrobial, phytotoxic, or insecticidal activity.

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Recent studies have defined a data-collection protocol and a metric that provide a robust measure of global radiation damage to protein crystals. Using this protocol and metric, 19 small-molecule compounds (introduced either by cocrystallization or soaking) were evaluated for their ability to protect lysozyme crystals from radiation damage. The compounds were selected based upon their ability to interact with radiolytic products (e.g. hydrated electrons, hydrogen, hydroxyl and perhydroxyl radicals) and/or their efficacy in protecting biological molecules from radiation damage in dilute aqueous solutions. At room temperature, 12 compounds had no effect and six had a sensitizing effect on global damage. Only one compound, sodium nitrate, appeared to extend crystal lifetimes, but not in all proteins and only by a factor of two or less. No compound provided protection at T=100 K. Scavengers are ineffective in protecting protein crystals from global damage because a large fraction of primary X-ray-induced excitations are generated in and/or directly attack the protein and because the ratio of scavenger molecules to protein molecules is too small to provide appreciable competitive protection. The same reactivity that makes some scavengers effective radioprotectors in protein solutions may explain their sensitizing effect in the protein-dense environment of a crystal. A more productive focus for future efforts may be to identify and eliminate sensitizing compounds from crystallization solutions.

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In order to accurately measure the photon flux and to assist in aligning the beam, we have designed a modified beam stop device based on a photo diode integrated with the beam stop. The beam stop contains a small CdWO(4) crystal that completely stops the X-rays and at the same time produces photoluminescence proportional to the X-ray flux. The light is then guided to a photosensitive diode, using a flexible light pipe, to monitor the flux. With this device we achieve the goal of stopping the primary X-ray beam and simultaneously monitoring the X-ray intensity, thus eliminating the need for integrating ion-chambers into the capillary or collimator mount.

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Crystallization of proteins is important for fundamental studies and biopharmaceutical development but remains largely an empirical science. Here, we report the use of organic salts that can form a class of unusual nonamphiphilic lyotropic liquid crystals to crystallize the protein lysozyme. Certain nonamphiphilic organic molecules with fused aromatic rings and two charges can assemble into stable thread-like noncovalent polymers that may further form liquid crystal phases in water, traditionally termed chromonic liquid crystals. Using five of these mesogenic molecules as additives to induce protein crystallization, we discover that molecules that can form liquid crystal phases in water are highly effective at inducing the crystal formation of lysozyme, even at concentrations significantly lower than that required for forming liquid crystal phases. This result reveals an example of inducing protein crystallization by the molecular assembly of the additives, and is consistent with a new mechanism by which the strong hydration of an assembly process provides a gradual means to compete for the water molecules to enable solvated proteins to form crystals.

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The Macromolecular Diffraction Facility at the Cornell High Energy Synchrotron Source (MacCHESS) is a national research resource supported by the National Center for Research Resources of the US National Institutes of Health. MacCHESS is pursuing several research initiatives designed to benefit both CHESS users and the wider structural biology community. Three initiatives are presented in further detail: microcrystallography, which aims to improve the collection of diffraction data from crystals a few micrometers across, or small well diffracting regions of inhomogeneous crystals, so as to obtain high-resolution structures; pressure cryocooling, which can stabilize transient structures and reduce lattice damage during the cooling process; and BioSAXS (small-angle X-ray scattering on biological solutions), which can extract molecular shape and other structural information from macromolecules in solution.

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The synthesis, structural, and spectral characterization as well as a theoretical study of a family of alkaline-earth-metal acetylides provides insights into synthetic access and the structural and bonding characteristics of this group of highly reactive compounds. Based on our earlier communication that reported unusual geometry for a family of triphenylsilyl-substituted alkaline-earth-metal acetylides, we herein present our studies on an expanded family of target derivatives, providing experimental and theoretical data to offer new insights into the intensively debated theme of structural chemistry in heavy alkaline-earth-metal chemistry.

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The red, five-coordinate complexes Ru(CO)Cl(PPh(3))2(CH=CHPh) and [Ru(CO)Cl(PPh(3))2]2(mu-CH=CHC(6)H(4)CH=CH) undergo reversible coordination of PPh(3) at low temperature to produce the pale yellow, six-coordinate complexes Ru(CO)Cl(PPh(3))3(CH=CHPh) and [Ru(CO)Cl(PPh(3))3]2(mu-CH=CHC(6)H(4)CH=CH). X-ray crystal structures of the latter complex and of the hydride complex RuH(CO)Cl(PPh(3))3 were obtained. 1H and 31P NMR spectra between 20 and -70 degrees C exhibit large changes in both equilibrium constants and dynamic effects. Thermodynamic parameters, DeltaH = -17.5 +/- 2.0 kcal/mol and DeltaS = -57.5 +/- 7.6 eu, were obtained for PPh(3) coordination to the monoruthenium complex, and activation parameters, DeltaH = 20.6 +/- 0.7 kcal/mol and DeltaS = 41.6 +/- 2.0 eu, were obtained for the reverse decoordination. Coordination of PPh(3) was not observed upon cooling of the shorter bridged complex, [Ru(CO)Cl(PPh(3))2]2(mu-CH=CHCH=CH).

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Four novel alkaline earth metal tetranuclear aryloxide/pyrazolate hydroxides of the general formula M4(ligand)6(OH)2(donor)n have been prepared by either adding stoichiometric quantities of water to preformed alkaline earth metal aryloxides or in a direct metalation regime combining metal, ligand (alcohol, pyrazole), and donor with stoichiometric amounts of water. The compounds are considered as potential intermediates in the sol-gel process. A nonhydrolyzable magnesium aryloxide has also been obtained using the same reaction scheme. Unexpectedly, a dimeric strontium complex with further association of a second dimer via hydrogen bonding from the solvent of crystallization, ethylenediamine, has been isolated by the treatment of strontium metal with a mixture of alcohol and water. All compounds were characterized using X-ray crystallography, 1H and 13C NMR, and IR spectroscopy.

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To bridge the gap between traditional multilayer and crystal optics a high-resolution multilayer monochromator with a bandwidth of 0.22% has been designed and installed on a bending-magnet beamline (F3) at the Cornell High Energy Synchrotron Source (CHESS) to provide an unfocused monochromatic X-ray beam for protein crystallography experiments. Crystallographic data of excellent quality from a medium-sized protein, Concanavalin A, were collected and processed using standard crystallographic programs. The data were successfully used for a structure solution and refinement. The flux from the multilayer monochromator is enhanced, relative to that from a flat Si(111) monochromator, by a factor of 5; consequently, data collection is faster and/or smaller samples may be used. At the same time, the bandwidth is narrow enough to avoid streaked spots. This experiment suggests that multilayer optics may play a valuable role in satisfying the demands of the structural biology community for rapid X-ray data collection, particularly at under-utilized bending-magnet beamlines.

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Novel alkaline earth metal aryl-substituted silylamides were prepared using alkane (Mg) and salt elimination reactions (Mg, Ca, Sr, and Ba). The salt elimination regime involved the treatment of the alkaline earth metal iodides with 2 equiv of the respective potassium amide KNDiip(SiMe(3)), (Diip = 2,6-i-Pr(2)C(6)H(3)). The organomagnesium source for the alkane elimination was ((n)()Bu/(s)()Bu)(2)Mg. All compounds were characterized using (1)H, (13)C NMR, and IR spectroscopy, in addition to X-ray crystallography (except Mg[NDiip(SiMe(3))](2)THF(2)). Crystal data with Mo Kalpha (lambda = 0.710 73 A) are as follows: Mg[NDiip(SiMe(3))](2), 1, a = 9.4687(6) A, b = 9.6818(6) A, c = 17.9296(1) A, alpha = 96.487(1) degrees, beta = 94.537(1) degrees, gamma = 89.222(1) degrees, V = 1608.8(2) A(3), Z = 2 (two independent molecules), triclinic, space group P(-)1, R1 (all data) = 0.0508; (n)()BuMg[NDiip(SiMe(3))]THF(2), 2, a = 9.5413(1) A, b = 16.493(2) A, c = 9.8218(1) A, beta = 108.149(2) degrees, V = 1468.7(4) A(3), Z = 2, monoclinic, space group P2(1), R1(all data) = 0.1232; Ca[NDiip(SiMe(3))](2)THF(2), 4, a = 9.7074(1) A, b = 20.9466(4) A, c = 21.6242(3) A, alpha = 73.573(1) degrees, beta = 78.632(1) degrees, gamma = 89.621(1) degrees, V = 4129.1(1) A(3), Z = 4 (two independent molecules), triclinic, space group P(-)1, R1 (all data) = 0.0902; Sr[NDiip(SiMe(3))](2)THF(2), 5, a = 20.5874(5) A, b = 9.8785(2) A, c = 20.8522(5) A, beta = 102.035(2) degrees, V = 4147.6(2) A(3), Z = 4 (two independent molecules), monoclinic, space group P2/n, R1 (all data) = 0.0756; Ba[NDiip(SiMe(3))](2)THF(2), 6, a = 20.5476(2) A, b = 10.0353(2) A, c = 20.9020(4) A, beta = 101.657(1) degrees, V = 4221.0(1) A(3), Z = 4 (two independent molecules), monoclinic, space group P2/n, R1 (all data) = 0.0573.

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The synthesis and structural characterization of two magnesium thiolate complexes are described. Both compounds were prepared by analogous reactions routes, namely, alkane elimination and transamination, but using differently sized ligands. Utilization of the smaller HSCPh(3), resulted in the formation of [Mg(15-crown-5)(SCPh(3))(2)], 1, displaying a seven-coordinate magnesium center with two magnesium-sulfur bonds. Employment of the sterically more encumbered HS-2,4,6-tBu(3)C(6)H(2) yielded a separated cation and anions as displayed in [Mg(15-crown-5)(THF)(2)][S-2,4,6-tBu(3)C(6)H(2)](2), 2. Compound 2 exhibits a seven-coordinate cation, completing its coordination environment with five metal-crown-ether interactions in addition to two tetrahydrofuran (THF) contacts. The compounds were characterized by IR and NMR spectroscopy in addition to X-ray crystallography. Crystal data with Mo Kalpha (lambda = 0.710 73 Å) are as follows: 1, C(48)H(50)MgO(5)S(2), a = 8.4785(4) Å, b = 9.3595(5) Å, c = 13.8306(6) Å, alpha = 87.332(1) degrees, beta = 85.929(1) degrees, gamma = 68.733(1) degrees, Z = 1, triclinic; 2, C(54)H(94)MgO(7)S(2), a = 13.6755(2) Å, b = 12.8045(6) Å, c = 32.7127(12) Å, beta = 97.87(1) degrees, Z = 4, monoclinic.

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An unprecedented ligand bending mode is displayed by the acetylide ligands in the first structurally characterized σ-bound organometallic strontium and barium complexes [M([18]crown-6)(CCSiPh3 )2 ] (M=Sr, Ba). Furthermore, the observed decrease of the angle at the sp-hybridized C atom on descending Group 2 (see structures depicted) affords new information that will lead to a better understanding of the bonding in alkaline earth metal compounds.

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A series of highly reactive heavy alkali metal phosphides was prepared by treating trimethylsilyl-substituted phosphines with alkali metal tert-butyl alcoholates. The compounds are formed in excellent yield and purity, and the side product can be easily removed in a vacuum. The high synthetic potential of this reaction route was further shown by utilizing excess alkali metal tert-butyl alcoholates in reaction with silyl substituted phosphines. In all cases, only monometalated products were isolated. In the course of this work the crystal structures of the bis(trimethylsilyl)phosphides [K(thf)P(SiMe(3))(2)](infinity), 1a, [Rb(thf)P(SiMe(3))(2)](infinity), 1b, and [Cs(thf)P(SiMe(3))(2)](infinity), 1c, were obtained. The compounds display polymeric ladder-type structures. Compounds 1a,b are isomorphous, while compound 1c displays a slightly altered local geometry. Despite small differences in local geometry, the coordination spheres for the phosphorus atoms and the alkali metal are fairly similar. The five coordinate phosphorus atoms are connected to three alkali metal centers in addition to two trimethylsilyl groups. The alkali metals are four coordinate with ligations to three phosphorus centers in addition to one thf oxygen donor. Compounds 1a-c were characterized using elemental analysis, NMR spectroscopy, and X-ray crystallography. Crystal data with Mo Kalpha (lambda = 0.710 73 Å) at 150 K are as follows: 1a, a = 6.4261(2) Å, b = 12.4119(2) Å, c = 21.5447(4) Å, V = 1718.41(7) Å(3), Z = 4, orthorhombic, space group P2(1)2(1)2(1), 3427 independent reflections, R1 (all data) = 0.0351; 1b, a = 6.5338(2) Å, b = 12.5664(3) Å, c = 21.5537(5) Å, V = 1769.70(8) Å(3), Z = 4, orthorhombic, space group P2(1)2(1)2(1), 4195 independent reflections, R1 (all data) = 0.0776; 1c, a = 11.3515(1) Å, b = 22.3445(3) Å, c = 7.2501(1) Å, beta = 96.017(1) degrees, V = 1828.81(4) Å(3), Z = 4, monoclinic, space group P2(1)/c, 4343 independent reflections, R1 (all data) = 0.0811.

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The exploration of synthetic methodologies toward heavy alkaline-earth chalcogenolates resulted in the preparation and structural characterization of a family of calcium thiolates, including [Ca(SC(6)F(5))(2)(py)(4)], 1 (py = pyridine), the separated ion-triple [Ca(18-crown-6)(NH(3))(3))][SMes](2).2THF, 2 (Mes = 2,4,6-tBu(3)C(6)H(2)), and the contact triple [Ca(18-crown-6)(SMes)(2)].THF, 3. Compound 1 was prepared by treating [Ca(N(SiMe(3))(2))(2)](2) with 4 equiv of HSC(6)F(5) under addition of pyridine. The thiolates 2 and 3 were synthesized by treatment of calcium metal dissolved in dry, liquid NH(3) under addition of 2 equiv of HSMes and crown ether or, alternatively, by the reduction of MesSSMes with calcium metal in dry, liquid ammonia. We also report two reaction products isolated during attempted calcium thiolate syntheses: [CaBr(4)(THF)(2)(&mgr;(2)-Li)(2)(THF)(4)], 4, isolated as the product of a salt elimination reaction between CaBr(2) and 2 equiv of [Li(THF)(n)()S-2,4,6-(i)()Pr(3)C(6)H(2)](m)(). [(NH(4))(py)(SC(6)F(5))], 5, was obtained as the sole product in the reaction of metallic calcium with HSC(6)F(5) in liquid ammonia under addition of pyridine. All compounds were characterized by single-crystal X-ray crystallography in addition to IR and NMR spectroscopy.

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A side reaction leads to the product. In the synthesis of [{Be(SPh)2 (py)(NH3 )}2 {[18]crown-6}] (1, py=pyridine) from [Be{N(SiMe3 )2 }2 ] and HSPh, the coordinated ammonia molecules (see the structure of 1 in the picture) are formed in a competing reaction between liberated hexamethyldisilazane and the thiol.