Synthesis of a peptidomimetic tricyclic tetrahydrobenzo[ij]quinoline as a VLA-4 antagonist.
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Aluminum Compounds↗
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Feasibility study on epithermal neutron field for cyclotron-based boron neutron capture therapy.
To realize the accelerator-based boron neutron capture therapy (BNCT) at the Cyclotron and Radioisotope Center of Tohoku University, the feasibility of a cyclotron-based BNCT was evaluated. This study focuses on optimizing the epithermal neutron field with an energy spectrum and intensity suitable for BNCT for various combinations of neutron-producing reactions and moderator materials. Neutrons emitted at 90 degrees from a thick (stopping-length) Ta target, bombarded by 50 MeV protons of 300 microA beam current, were selected as a neutron source, based on the measurement of angular distributions and neutron energy spectra. As assembly composed of iron, AlF3/Al/6LiF, and lead was chosen as moderators, based on the simulation trials using the MCNPX code. The depth dose distributions in a cylindrical phantom, calculated with the MCNPX code, showed that, within 1 h of therapeutic time, the best moderator assembly, which is 30-cm-thick iron, 39-cm-thick AlF3/Al/6LiF, and 1-cm-thick lead, provides an epithermal neutron flux of 0.7 x 10(9) [n cm(-2) s(-1)]. This results in a tumor dose of 20.9 Gy-eq at a depth of 8 cm in the phantom, which is 6.4 Gy-eq higher than that of the Brookhaven Medical Research Reactor at the equivalent condition of maximum normal tissue tolerance. The beam power of the cyclotron is 15 kW, which is much lower than other accelerator-based BNCT proposals.
Aluminum Compounds↗
[Reduction of ethyl oxalate by lithium aluminum hydride].
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Aluminum Compounds↗
Identification of urinary metabolites of cannabidiol in the dog.
Three dogs were treated with cannabidiol (CBD) and urine samples were collected periodically to 30 hr. Metabolites were extracted with ethyl acetate before and after hydrolysis with beta-glucuronidase, and examined by GC/MS,. Thirty-seven metabolites were identified and another nine partially characterized. Twenty-one of the identified metabolites have not been reported before for this drug. The major oxidative metabolic routes were 6-hydroxylation, both alpha and beta, and beta-oxidation. At 10 hr the major metabolites of this type were 6-hydroxy-4'',5''-bis,nor-CBD-3''-oic acid and 6-oxo-4'',5''-bis,nor-CBD-3''-oic acid, whereas at 22 hr, further beta-oxidation had occurred to give 6-hydroxy-2'',3'',4'',5''-tetrakis,nor-CBD-1"pr-oic acid as the major metabolite. Other metabolic routes were carboxylic acid formation at C-7 accompanied by hydroxylation in the side chain, and dihydroxylation of the C-8,9 double bond. Three compounds, 4''-hydroxy-CBD, 5''hydroxy-CBD, and 6-oxo-CBD were found at early times as glucose conjugates in concentrations that exceeded those of the other metabolites. The unconjugated forms of these metabolites were not found and none of the identified oxidized metabolites were found as glucosides. Only 4'',6-dihydroxy-CBD was found conjugated with glucuronic acid.
Aluminum↗
Urinary metabolites of cannabidiol in dog, rat and man and their identification by gas chromatography-mass spectrometry.
Urinary metabolites of cannabidiol (CBD), a non-psychoactive cannabinoid of potential therapeutic interest, were extracted from dog, rat and human urine, concentrated by chromatography on Sephadex LH-20 and examined by gas chromatography-mass spectrometry as trimethylsilyl (TMS), [2H9]TMS, methyl ester-TMS and methyloxime-TMS derivatives. Fragmentation of the metabolites under electron-impact gave structurally informative fragment ions; computer-generated single-ion plots of these diagnostic ions were used extensively to aid metabolite identification. Over fifty metabolites were identified with considerable species variation. CBD was excreted in substantial concentration in human urine, both in the free state and as its glucuronide. In dog, unusual glucoside conjugates of three metabolites (4"- and 5"-hydroxy- and 6-oxo-CBD), not excreted in the unconjugated state, were found as the major metabolites at early times after drug administration. Other metabolites in all three species were mainly acids. Side-chain hydroxylated derivatives of CBD-7-oic acid were particularly abundant in human urine but much less so in dog. In the latter species the major oxidized metabolites were the products of beta-oxidation with further hydroxylation at C-6. A related, but undefined pathway resulted in loss of three carbon atoms from the side-chain of CBD in man with production of 2"-hydroxy-tris,nor-CBD-7-oic acid. Metabolism by the epoxide-diol pathway, resulting in dihydro-diol formation from the delta-8 double bond, gave metabolites in both dog and human urine. It was concluded that CBD could be used as a probe of the mechanism of several types of biotransformation; particularly those related to carboxylic acid metabolism as intermediates of the type not usually seen with endogenous compounds were excreted in substantial concentration.
Aluminum↗
Reduction of fatty acid methyl esters to fatty alcohols to improve volatility for isotopic analysis without extraneous carbon.
Carbon in derivatization groups cannot be distinguished from analyte carbon by chromatography-based high-precision compound-specific or position-specific isotope analysis. We report the reduction of fatty acid methyl esters to fatty alcohols to facilitate high-quality chromatographic separation, without addition of extraneous carbon, with subsequent high-precision position-specific isotope analysis. Methyl palmitate is quantitatively reduced to 1-hexadecanol by LiAlH4 in a one-step reaction. Gas-phase pyrolysis of 1-hexadecanol results in a series of monounsaturated alcohols and alpha-olefins analogous to fragmentation found for methyl palmitate, as well as an additional peak corresponding to the pyrolytic dehydration product, 1-hexadecene. Carbon isotope analysis of the fragments yielded precision of SD (delta 13C) < 0.4/1000. Results of position-specific analysis of very low enrichment [1-13C]-1-hexadecanol (delta 13C = -4.00/1000) showed no evidence of scrambling of the C1 position, and isotope ratios in accord with expectations. The pyrolysis product 1-hexadecene was isotopically enriched relative to 1-hexadecanol, which may cause minor depletion of other pyrolysis products that can be taken into account by routine calibration. The procedure is general and can be extended to compound-specific and position-specific analysis of moderate molecular weight, low-volatility analytes containing acid groups that would otherwise be blocked with methyl, ethyl, acetyl, or trimethyl silyl groups containing extraneous carbon.
Aluminum Compounds↗
In situ complexation of lithium chloride by amphiprotic cyclophosphazenes.
The amphiprotic cyclophosphazene [CH3O(CH2)3NH]6P3N3 (1) incorporates lithium chloride via successive protonation with HCl and deprotonation with Bu(n)Li (or vice versa) to generate the coordination polymer 1.2LiCl, a molecular model compound for lithium ion containing solid polymer electrolytes.
Journal Article↗
A highly selective bicyclic fluoroionophore for the detection of lithium ions.
The macrobicyclic molecule, 21-(9-anthrylmethyl)-4,17,13,16-tetraoxa-1,10,21-triazabicyclo [8.8.5]tricosane-19,23-dione, I, was designed, synthesized and characterized as a fluoroionophore for the selective, optical detection of lithium ions. Compound I is based on a bridged diazacrown structure, which provides a semirigid binding framework. Binding takes place by electrostatic interactions between the oxygen atoms of the crown and the cation and is transduced to fluorescence emission from an attached anthracene fluorophore. In a 75:25 dichloromethane/tetrahydrofuran solvent mixture, I acts as an intramolecular electron transfer "off-on" fluorescence switch, exhibiting a greater than 190-fold enhancement in fluorescence emission intensity in the presence of lithium ions. The relative selectivity of I for lithium ions over sodium, potassium and ammonium ions was found to be log K(Li+,Na+) approximately -3.36, log K(Li+,K+) approximately -1.77 and log K(Li+,NH4+) approximately -2.78.
Bridged Bicyclo Compounds, Heterocyclic↗
Synthesis, properties and reactions of 3 beta-benzoyloxy-7 alpha-15 beta-dichloro-5 alpha-cholest-8(14)-ene.
Treatment of 3 beta-benzoyloxy-14 alpha,15 alpha-epoxy-5 alpha-cholest-7-ene (I) with gaseous HCl in chloroform at -40 degrees C gave, in 87% yield, 3 beta-benzoyloxy-7 alpha,15 beta-dichloro-5 alpha cholest-8(14)-ene (III). Reduction of the latter compound with lithium aluminum hydride in ether at room temperature for 20 min gave, in 86% yield, 7 alpha-15 beta-dichloro-5 alpha-cholest-8(14)-en-3 beta-ol (IV). The latter compound was fully characterized and assignments of the individual carbon peaks in the 13C nuclear magnetic resonance spectra of this sterol have been completed. Reduction of III with excess lithium aluminum hydride in refluxing ether for 4 days gave, in 74% yield, 5 alpha-cholesta-7,14-dien-3 beta-ol (VI). Reduction of the dichloro-steryl benzoate III with lithium triethylborohydride in tetrahydrofuran gave, in 88% yield, 5 alpha-cholest-8(14)-en-3 beta-ol (VII). A similar reduction using lithium triethylborodeuteride led to the formation of [7 beta, 15 xi-2 H2]-VIIa. Treatment of III with concentrated HCl in a mixture of chloroform and methanol gave, in 79% yield, 3 beta-benzoyloxy-5 alpha-cholest-8(14)-en-15-one (II) which was characterized as such and as the corresponding free sterol.
L Cells↗
Quinobene, a new potent anti-HIV agent.
A simple synthesis of the sulfonated azo dye Quinobene (3) and its derivatives, as well as the results of their evaluation in anti-HIV screening have been described. Thus, reacting the diazonium salt of 4,4'-diaminostilbene-2,2'-disulfonic acid with 8-hydroxyquinoline-5-sulfonic acid yielded the readily isolable title compound. The lithium and tetramethylammonium salts of Quinobene and its complexes with Cu(II), Zn(II), Mg(II) were also prepared. In vitro tests showed considerable activity of these compounds against HIV-1.
Antiviral Agents↗
X-ray and neutron diffraction studies on "Li4.4Sn".
A chemical analysis and detailed structural characterization, using X-ray single crystal and neutron powder diffraction, of the binary lithium-tin compound "Li(4.4)Sn" is presented. Phase analyses and subsequent structural refinements result in the reformulation of "Li(4.4)Sn" as Li(17)Sn(4). The lithium-rich binary phase crystallizes with a complex cubic structure in the space group Ffourmacr;3m, with a = 19.6907(11) A, Z = 20. The improved crystal structure determination indicates well-defined lithium atom positions, some of which differ from those previously reported. The nearly Zintl phase Li(17)Sn(4) exhibits poor metallic behavior similar to that of heavily doped semiconductors. Comparisons of the refined crystal structure with previously reported X-ray crystal structures associated with "Li(4.4)Sn" are discussed.
Journal Article↗
NMR spectroscopy of organolithium compounds. XXVI--The aggregation behaviour of methyllithium in the presence of LiBr and LiI in diethyl ether and tetrahydrofuran.
1H, 6Li and 13C NMR spectroscopy were used to determine the structure of aggregates formed in mixtures of methyllithium, H3CLi, and lithium bromide and iodide in diethyl ether and tetrahydrofuran. From the chemical shifts, the signal intensity distribution and the isotope shifts observed for partially deuterated systems, it was shown that generally tetrameric structures with different halogen contents dominate. For methyllithium-lithium bromide (1:1) in THF a considerable concentration of an H3CLi-LiBr dimer was found. For the first time, deuterium-induced 6Li isotope shifts over four bonds were observed.
Bromides↗
Wetting characteristic of ceramic to water and adhesive resin.
STATEMENT OF PROBLEM: Maximum wetting of ceramic by adhesive resin is required to achieve optimal adhesion of the resin to ceramic. It is unknown whether the adhesion of the resin to the ceramic is affected by the surface topography and wetting by water or the adhesive resin. PURPOSE: This study was designed to characterize the effect of surface topography on the wetting of ceramics by water and adhesive resin. MATERIALS AND METHODS: Three materials, a veneering ceramic, Eris (ERV), and 2 core ceramics, Empress 1 core ceramic (E1C) and an experimental core ceramic (EXC), were used. Four surface-roughening procedures were used. They included polishing through 1200-grit SiC paper (P), air abrasion with 50 microm Al(2)O(3) (A), etching with 5% hydrofluoric acid gel (E), and a combination of airborne particle abrasion and etching (A/E). Forty bar specimens (15 x 10 x 1.5 mm) were prepared from each material (N=120). Twelve groups of 10 specimens each were prepared for the 4 surface-roughening procedures. Advancing (theta(A)) and receding (theta(R)) contact angles were measured with a CAHN Dynamic Contact Analyzer, on the basis of the Wilhelmy plate technique, with water and adhesive resin. The work of adhesion (W(A)) by the probing media was calculated by use of advancing contact angle data. The data were analyzed by t testing, analysis of variance, and Duncan's tests (alpha=0.05) to determine the statistical significance of differences in the contact angles between ceramic and water or resin as a function of surface roughening. RESULTS: In general, the mean theta(A) values were higher than the mean theta(R) values except for groups of E or A/E specimens with water used as a probing medium. E and A/E treatments yielded the lowest contact angle values, followed by A and P treatments (P<.001). The E1C exhibited the highest mean contact angles, whereas EXC exhibited the lowest mean contact angle except for the theta(R) with resin. The corresponding values for ERV were between those of E1C and EXC except for theta(R) values with resin. The resin medium yielded higher mean contact angles than the water medium for the same surfaces. W(A) ranged from 62.9 to 145.2 mJ/m(2). CONCLUSIONS: Within the limitations of this study, etching or a combination of air abrasion and etching were comparably effective in increasing the surface area for bonding. The most wettable surface as measured by the resin medium was EXC, followed by ERV and E1C.
Acid Etching, Dental↗
Oxidative cleavage of the pentyl side-chain of cannabinoids. Identification of new biotransformation pathways in the metabolism of 4'-hydroxy-delta-9-tetrahydrocannabinol in the mouse.
During an investigation of the mechanisms leading to the formation of metabolites of cannabinoids in which the pentyl side chain is reduced to 2, 3 or 4 carbon atoms, the further metabolism of 4'-hydroxy-delta 9-tetrahydrocannabinol was investigated in vivo in mice. Metabolites were extracted with ethyl acetate, concentrated by chromatography on Sephadex LH-20 and identified by GC/MS. Ten metabolites were identified and a further two had tentative structural assignments made. The major metabolic route, in common with that seen with most cannabinoids, was hydroxylation at the allylic 11-position, followed by oxidation to a carboxylic acid. Additional hydroxylation occurred at C-8. Abundant metabolites were also formed by oxidative cleavage of the pentyl side chain. The major metabolites of this type had lost the terminal two carbon atoms to give compounds containing a carboxyethyl side chain. This is the major product normally produced by beta-oxidation of the acid formed from 5'-hydroxy-delta 9-tetrahydrocannabinol. Trace concentrations of two other acids that appeared to have a carboxypropyl side chain were also found. The results show that, in addition to beta-oxidation, initiated by hydroxylation at the 5'-carbon atom (omega-hydroxylation), at least one other oxidative route, initiated by omega-1-hydroxylation, is involved in the production of metabolites with two carbon atoms missing from the pentyl side chain. This pathway does not seem to have been characterized as a biotransformation mechanism in drug metabolism and a possible mechanism is suggested.
Aluminum↗
Tardive dyskinesia: nondopaminergic treatment approaches.
The continuing concern about tardive dyskinesia (TD) has stimulated a broad search for therapies for this disorder. Since neuroleptic drugs are thought to be the etiological agents, acting presumably through dopamine receptor blockade, nondopaminergic drugs have been the focus of recent study. However, no uniformly safe and effective drug treatment has been identified. Augmentation of cholinergic function is theoretically attractive, but further research is needed to develop practical and effective compounds. GABA drugs do not consistently suppress TD. The effect of benzodiazepines in TD is unclear, but these agents may be of some temporary benefit in patients with distressing symptoms. Lithium, serotonergic compounds, and numerous neuropeptides all fail to have any consistent effect in TD. Early reports of benefit with alpha- and beta-noradrenergic agents are interesting but require further study. Many other drug types have been tried without benefit. For the majority of patients, it may be best to give no drug treatment. Any drug that is capable of suppressing TD may aggravate the disorder in the long term. The potential for a spontaneous gradual remission of TD is an argument in favor of a patient, nonaggressive, and cautiously optimistic approach to this disorder.
Basal Ganglia↗
Effects of lithium carbonate on cytokine production in patients affected by breast cancer.
It has been reported that lithium salt compounds influence hematopoiesis, which is known to be regulated by a number of cytokines, including tumor necrosis factor (TNF), interleukin-1 (IL-1) and interleukin-6 (IL-6). Since lithium can induce TNF production in human monocytes, we wished to determine if lithium carbonate treatment of neutropenic patients affected by breast cancer results in increased cytokine production. Serum levels of TNF alpha, IL-1 and IL-6 were measured before and at 7 and 180 days after treatment with lithium carbonate. Results indicate that this therapy produced TNF alpha and IL-6, but not IL-1 alpha, elevations in patients affected by unmetastasized breast cancer. Conversely, TNF alpha, but not IL-6, elevations were detected in metastatic patients. Studies are under way to investigate the mechanisms by which lithium salts affect cytokine production in monocytes from cancer patients.
Aged↗
Rationally designed non-peptides: variously substituted piperazine libraries for the discovery of bradykinin antagonists and other G-protein-coupled receptor ligands.
Molecular modeling studies of potent decapeptide bradykinin antagonists suggested the de novo design of peptide mimetics based on a 1,2,3,4-tetrasubstituted 1,4-piperazin-6-one scaffold. These de novo-designed antagonists exhibited only modest potency (IC50 approximately 55 microM) on a cloned human B2 receptor and antagonist activity in an in vitro human-cell functional assay. The success of these structures led to the creation of prototype libraries based on variously substituted 1,4-piperazine scaffolds, which allowed a rapid and general search of pharmacophores attached to a piperazine scaffold. The parent piperazinedione structures and fully reduced piperazine libraries differ from recently reported diketopiperazine libraries in the use of diverse nonnatural amino acids, on-resin-submonomer synthesis to provide more diverse N-substituted structures, and the adaptation of simultaneous ring closure and resin cleavage to drive the formation of highly hindered amide bonds. Using this chemistry, a rationally directed non-peptide library of approximately 2500 N,N'-disubstituted piperazines and piperazinediones was synthesized and screened for ligand affinity on bradykinin, neurokinin, and opioid receptors. A number of lead structures were identified. Notably, a bradykinin antagonist lead, CP-2458, with good receptor selectivity and antagonist activity in human-cell assays was identified and is undergoing optimization by traditional and combinatorial methods.
Acetylation↗
In vivo desaturation of cis-delta 9-monounsaturated to cis-delta 9,12-diunsaturated alkenylether glycerolipids.
Plants convert lipid-bound cis-n-9 monoenoic to polyenoic fatty acid residues without involvement of corresponding CoA-thioesters. To provide additional evidence for this type of lipid-linked desaturation we incubated sn-1-O- and 2-O-(cis-9)octadecenylglycerol isomers with photoautotrophic cell cultures from tomato. After 14 days the fractions of phosphatidylcholine and monogalactosyldiacylglycerol were isolated and the incorporated glycerol ether backbones released by treatment with LiAlH4 (reduction of ester bonds) and short acid hydrolysis (cleavage of enol ether bonds). High performance liquid chromatography and mass spectroscopy of the products in appropriately derivatized form showed that the (cis-9)octadecenyl group in the sn-1 position of the phospholipid was nearly completely desaturated to a (cis-9,12)octadecadienyl residue having the same double bond arrangement as linoleic acid. In the galactolipid fraction the desaturation had progressed to octadecatrienyl residues. Similarly, the octadecenyl residue in the sn-2 position of the phospholipid was nearly completely desaturated to an octadecadienyl group. These results are unambiguous proof for lipid-linked desaturation by both microsomal and plastidial desaturase systems of plants.
Aluminum Compounds↗