Standard Reference Compounds Research Articles

A new class of inhibitors of secretory phospholipase A 2: enolized 1,3-dioxane-4,6-dione-5-carboxamides

Enolized 1,3-dioxane-4,6-dione-5-carboxamides a were identified as a new class of inhibitors of secretory phospholipase A 2 from human polymorphonuclear leucocytes (h-PMN PLA 2). Among the more than 30 compounds synthesized, the most potent inhibitors (IC 50 0.6–10 μM) were found in the series of 2,4-disubstituted phenyl analogues of a. Compound 1a was selected for evaluation of its biological profile. This substance potently inhibited secretory PLA 2s from several sources other than human PMNs, with a clear preference for group II over group I PLA 2, whereas human cytosolic PLA 2 and phospholipase C were not significantly affected. Inhibition of h-PMN PLA 2 was calcium-dependent. In intact mammalian cells stimulated in vitro, the release of arachidonic acid and the generation of prostaglandins and leukotrienes were inhibited at concentrations compatible with inhibition of PLA 2 as an underlying mechanism. In animal models in vivo (carragheenan oedema, adjuvant arthritis, pertussis pleurisy) 1a showed antiinflammatory activity, although the effect was rather weak compared with standard reference compounds.

Bioassay and Chemical Analysis of Ambient Air Particulate Extracts Fractionated by Using Nonaqueous Anion-Exchange Solid Phase Extraction

Abstract A nonaqueous anion-exchange solid-phase extraction technique has been developed for analyzing participate extracts of ambient air samples and combustion source samples. The technique has been used for sample preparation and sample prefractionation in bioassay-directed fractionations. This technique employs an anion-exchange resin to separate complex particulate extracts into four discrete fractions, which are characterized as neutral/basic, polar neutral/weak acid, weak acid, and stronger acid components. Two ambient air particulate extracts from Boise, Idaho, were analyzed by the developed method. Both samples contain a high percentage of organic compounds associated with wood combustion. The average recoveries of mass and mutagenicity were 93.7±M 1.5% and 100.8; pm 2.3%, respectively. Qualitative chemical analysis of the resulting fractions by gas chromatography-mass spectrometry showed agreement with the chemical class fractionation predicted by the separation of standard reference compounds. ...

Comparative Plasma Levels of Doxepin and Desipramine in the Elderly*

Although tricyclic antidepressants remain a principal mode of treatment of depression in the elderly, concomitant medical illness in this subgroup creates particular concern regarding the safety of these drugs. Doxepin has gained favour for use in the geriatric population due to claims of low cardiovascular side effects. This perceived safety has been questioned, however, since few investigators have actually reviewed plasma levels. A recent finding of interest revealed that two patients on 150 mg of doxepin daily with assured compliance had undetectable levels of doxepin or desmethyldoxepin in their plasma. A prospective study was consequently undertaken to compare oral doses and plasma levels of doxepin with desipramine as a standard reference compound. Data was collected for 19 females (12 on doxepin, seven on desipramine) and 12 males (five on doxepin, seven on desipramine) with a mean age of 76. Eight patients on doxepin showed undetectable plasma levels as compared with none on desipramine. This is a highly significant difference. Although the therapeutic plasma range for doxepin remains controversial, it is unlikely that patients can respond to levels of zero. The authors recommend routine monitoring of doxepin levels in the elderly and question poor bioavailability or absorption of this tricyclic antidepressant in some patients.

Effect of triphenylacrylonitrile derivatives on estradiol-receptor binding and on human breast cancer cell growth

In a study of a series of 26 triphenylacrylonitrile derivatives (TPEs), we investigated the influence of several possibly interrelated factors on the proliferation of human breast cancer cell lines. (1) Chemical substituents: the test compounds were for the most part para-hydroxylated with increasingly bulky hydrophobic and/or basic side chains [isopropyloxy or (diethylamino)ethoxy] or standard reference compounds. (2) Relative binding affinities (RBAs): they competed diversely for [3H]estradiol (E2) binding to calf uterus cytosol and little, if at all, for binding to the [3H]tamoxifen-labeled antiestrogen binding site (AEBS) in lower speed supernatant. A multiparametric comparison of RBAs recorded for calf, rat, and mouse uterus cytosol estrogen receptor (ER) revealed a possible influence of species-specific receptor conformation and/or environment on binding. (3) Estrogen/antiestrogen potency: their stimulation and inhibition of the proliferation of the ER-positive human breast cancer cell line (MCF7) was measured. Compounds with only hydroxy substituents stimulated proliferation more markedly than methylated derivatives and had a maximum effect at 10(-11)-10(-6) M. Stimulation was related to the RBA for ER. Compounds with isopropyloxy or (diethylamino)ethoxy side chains only weakly stimulated MCF7 cell growth and more powerfully antagonized E2-promoted growth. The extent of inhibition depended upon the bulk of the side chain and could be reversed by 10(-7) M E2. Within the same concentration ranges, the test compounds were without effect on the BT20 ER-negative cell line. (4) Cytostatic and/or cytolytic activity: most compounds could arrest the proliferation of both MCF7 and BT20 cells at concentrations above 3 x 10(-6) M. This activity was thus independent of ER. Nevertheless, those compounds with a charged hydrophobic side chain, which were the most powerful antagonists of E2-promoted cell growth, were also the most cytotoxic. The overall results for all molecules on all parameters were submitted to a multivariate analysis (correspondence analysis) which revealed the progressive influence of increasing substitution by hydroxy and more bulky groups on the generation of antagonist activity and cytotoxicity.

Phosphane‐borane chemistry. Open‐chain and cyclic phosphane‐boranes based on tetramethyldiphosphane

Abstract1:2 addition compounds of tetramethyldiphosphane with BH3, BH2Br, BHBr2, and BBr3 (1a–d) have been prepared from the parent diphosphane and the dimethyl sulfide complexes of the boranes in the appropriate stoichiometric ratio. Open‐chain and cyclic phosphane‐borane cations were obtained from Me4P2 and H2BrB · SMe2 in the molar ratio 2:1 or 1:1, respectively: [Me2PPMe2 · BH2 · PMe2  PMe2]+Br− (2) or [H2B(Me2PPMe2)2‐ BH2]2+2Br− (3). Treatment of 1b with trimethylphosphane yields the salt [H2BrB·Me2PPMe2 · BH2 · PMe3]+Br− (4). – The crystal structures of 1b and 3 · 2MeOH have been determined by single‐crystal X‐ray diffraction methods. Molecules 1b have crystalographic C2h symmetry corresponding to the anti‐configuration of the diphosphane and staggered conformation of the BH2Br moieties. The monomers are arranged in layers with Br …︁ Br contacts of 3.66 Å. – Crystals of 3 · 2 MeOH have an ionic structure built from bromide ions, interstitial methanol molecules, and crystallographically centrosymmetric dications [H2B(Me2PPMe2)2‐BH2]2+. These dications are in a chair configuration approaching (non‐crystallographical) mirror symmetry. The intra‐ring valence angles at boron [116.2(2)°] are significantly larger than those at phosphorus (108.4°, average). The BP distances are shorter than in standard reference compounds (e.g. 1b), indicating extra stabilisation in the dicationic phosphane‐borane ring system. In the unit cell there are no sub‐van der Waals contacts between the individual components.

Effects of nitrosation on the chemical composition and epidermal carcinogenicity of the nitrogen-rich fraction of a high-boiling coal liquid.

An 800-850 degrees F solvent-refined coal-II liquid was fractionated into chemical classes to obtain the aliphatic hydrocarbons, polycyclic aromatic hydrocarbons (PAH), nitrogen-containing polycyclic aromatic compounds (NPAC), and hydroxy-substituted PAH (hydroxy-PAH). The isolated NPAC fraction was refractionated by chemical class both before and after undergoing a nitrosation reaction. The nitrosated and non-nitrosated refractionated NPAC fractions were further subfractionated into secondary amine (pyrroles), primary amine-enriched (amino-PAH), and tertiary amine (azaarene) classes. The PAH and hydroxy-PAH composition of the NPAC fraction increased upon nitrosation, whereas the amino-PAH fraction composition decreased upon nitrosation. Nitrosation of standards indicated the amino-PAH compounds reacted to form parent PAH, chloro-substituted PAH, and methoxy-substituted PAH when analyzed by high-resolution gas chromatography (GC) and GC/mass spectrometry (MS). Some easily oxidized PAH compounds reacted to form ketones and quinones. All other standard reference compounds, chosen to be representative of the major chemical classes of compounds present in coal liquefaction materials, were unchanged by the nitrosation reaction. The amino-PAH of the nitrosated NPAC fraction reacted to form parent and some chloro-substituted PAH when analyzed by low-voltage direct-probe MS in addition to the methods given above. Epidermal carcinogenesis studies with the PAH, NPAC, nitrosated NPAC, and hydroxy-PAH fractions isolated from the 800-850 degrees F coal liquid indicated the PAH and NPAC were the most important determiners of skin carcinogenesis, with the PAH giving a higher response than the NPAC. The tumorigenicity of the NPAC was drastically reduced by nitrosation, probably due to the destruction of the amino-PAH upon nitrosation.

Identification of homologous series of alkylated thiophenes, thiolanes, thianes and benzothiophenes present in pyrolysates of sulphur-rich kerogens

The ability of flash pyrolysis-gas chromatography with dual flame ionization and flame photometric detection, and flash pyrolysis-gas chromatography-mass spectrometry, to afford detailed information about the organic sulphur pyrolysis products of kerogens is exemplified through analysis of five different sulphur-rich, type II kerogens. The pyrolysates of these kerogens are extremely complex mixtures. The technique with flame photometric detection yields a chromatogram that shows the distribution of only organic sulphur products in the pyrolysates. However, a considerable loss of sensitivity in flame photometric detection was apparent for higher-molecular-weight compounds. The use of the mass spectrometer as a detector, using characteristic m/z values of organic sulphur compounds for appropriate mass chromatograms, was therefore preferable. Identification of the organic sulphur products was accomplished by sulphur-selective flame photometric detection and comparison of their mass spectral and chromatographic data with those of standard reference compounds. Chromatographic retention time data for 48 standard sulphur compounds (alkylated thiophenes, thiolanes and benzo[ b]thiophenes) were determined. Homologous series of 2-alkylthiophenes, 2-alkyl-5-methylthiophenes, 2-alkyl-5-ethylthiophenes, 2-alkylthiolanes, 2-alkylthianes, 2-alkyl-5-methylthiolanes, 2-alkyl-4-methylbenzo[ b]thiophenes, 4-alkyl-2-methylbenzo[ b]thiophenes and 2-alkyl-benzo[ b]thiophenes, through a total carbon number of 22, have been identified through linear Kováts plots and comparison of mass spectral and chromatographic data of the C 18 members of these series with those of standard compounds.

Sulphur heterocycles in coal-derived products: Relation between structure and abundance

Sulphur heterocycles in a coal tar and in a coal liquid vacuum residue were isolated by ligand exchange chromatography using PdCl 2 on silica gel. Subsequent fractions were analysed by capillary column gas chromatography and gas chromatography-mass spectrometry. Two new selective stationary phases (a smectic liquid-crystalline polysiloxane and a biphenyl polysiloxane), as well as a methylpolysiloxane, were used to resolve the numerous isomers. All major sulphur heterocycles with 3–6 rings were identified by comparison of retention times of mixture components with those of standard reference compounds. The structures and relative abundances of the major sulphur heterocycles were analogous to those of the major polycyclic aromatic hydrocarbons in the same or similar samples.

Micro conduction calorimeters to measure enthalpies of vaporization

Details of the construction of micro-conduction calorimeters for measuring enthalpies of vaporization (or sublimation) are described. Accuracy and precision of the calorimeters were tested by the use of a few standard reference compounds. Experimental results showed that the enthalpies of vaporization could be measured for compounds of vapor pressures of 10 Pa to 10 kPa at 298 K with uncertainty less than 0.2 per cent. Results of enthalpy of vaporization measurements for some compounds are also given. Since calorimetric cells of these calorimeters were composed of glass and PTFE, the calorimeters made it possible to measure the enthalpies of vaporization for metal corrosive compounds.

Lack of potency of metoclopramide's metabolites in various dopaminergic models

The dopaminergic properties of metoclopramide and four of its metabolites were determined in a series of in vivo and in vitro tests. In vivo measures included changes in dopamine turnover, serum prolactin levels and antagonism of apomorphine-induced stereotyped behavior. In each of these tests the four metabolites were either completely inactive or significantly less potent than the parent compound. The potency of metoclopramide and its metabolites in in vitro dopamine/neuroleptic receptor models was compared to the potency of standard reference compounds. In vitro results indicate that none of the four metabolites tested had antagonist activity in any of the receptor models in which they were evaluated. These findings will be discussed in light of the current understanding of receptor models as they relate to antipsychotic efficacy.

A review of the animal pharmacology of clobazam: An update

Clobazam is a 1, 5-benzodiazepine with significant activity in preclinical tests predictive of potential clinical antianxiety activity. Clinical efficacy equivalent to diazepam has been established with minimal effects on psychomotor performance. Clobazam has also been found to have a broad spectrum of anticonvulsant activity with acceptable toxicity and to be active in suppressing aggressive behavior in rodents. This compound appears to have less of an effect on motor coordination, muscle tone, behavioral depression and hyporeflexia than standard reference compounds in various species as well as little or no apparent effect on memory and learning in animals and humans. The major metabolite, desmethylclobazam, is also an anxiolytic candidate approximately 10 times less potent than diazepam and a potent anticonvulsant with a complete lack of sedation. These compounds represent a new classification of pharmaceutical agents in which antianxiety and anticonvulsant effects can be achieved without sedative or depressive side effects.

Substituent effects in the reaction of phenols with polyacrylonitrile radicals

Substituent effects in the reactivities of phenols towards polyacrylonitrile radicals have been studied in terms of Swain and Luptons' field ( F k) and resonance ( R k) components of the substituent parameters and the unique positional weighting factors ( f j and r j) proposed by Williams and Norrington, with the aid of the following equation: P i = x iƒ iF k + ß ir jK i + e i + P i o P i ′s are the rate parameters, P i 0 being that for a standard reference compound. Two types of rate parameters have been employed—one, suggested by Simonyi, Tüdös and Pospisil (β) and another, suggested by us, ( K), which is obtained from a plot of [Monomer]/(rate of polymerisation) vs [Phenol]. The correlations have been found to be quite satisfactory with both β and K. An attempt has been made to ascertain the nature of the transition state from the reaction parameters α i and β i ; a dipolar transition state is suggested. The anomalous kinetic behaviour of hydroxy phenols has been discussed.

Substituent effects in some autoxidation and hydrogen abstraction reactions in terms of their field (F) and resonance (R) components inclusive of unique positional weighting factors

Substituent effects in some autoxidation and hydrogen abstraction reactions have been studied in terms of the field (Fk) and resonance (Rk) components proposed by Swain and Lupton and the unique positional weighting factors fj and rj incorporated by Williams and Norrington with the aid of the following equation:[Formula: see text]where Pi's are the rate parameters, Pi0 being that for a standard reference compound. The correlations are found to be quite satisfactory, showing the general validity of the above equation for the types of reactions considered. From the information obtained from the present correlation studies, an attempt has been made to resolve the conflict with regard to the nature of the transition state involved in the hydrogen abstraction reactions – that is, whether or not there is charge separation in the transition state. The results of the present studies seem to suggest that both the differences in the resonance stabilization energies of the ring-substituted benzyl radical and the contribution of polar structures to the transition state are to be invoked to explain the observed data.

A dual ion-selective electrode detector for the simultaneous detection of bromine- and chlorine- containing compounds in gas chromatography

A dual ion-selective electrode gas chromatographic detector which allows the simultaneous detection of chlorine- and bromine-containing compounds through two-channel operation is described. Components eluted from the g.c. column are hydrogenated, the hydrogen chloride and hydrogen bromide produced being absorbed in a standard solution of halide; the ion concentrations in the resulting solution are monitored by chloride- and bromide-selective electrodes. The dual electrode detector gives two chromatograms simultaneously, one selective for chlorine- and bromine-containing compounds and the other for bromine-containing compounds. The response ratio, i.e., the peak area of the readout from the chloride channel divided by that from the bromide channel for the same compound, gives valuable information. The Cl/Br ratio in an eluted molecule can be determined accurately from the response ratio if a standard reference compound is injected simultaneously.

Isothermal Molecular Weight Determination: Apparatus, Procedure, and Study of Effect of Solvent and Standard on Accuracy and Precision

Abstract A study was made of the isothermal molecular weight determination; the apparatus constructed and the procedure developed are described. An extensive investigation was carried out to provide reliable guides for the selection of the correct solvents and standard reference compounds to be used in the molecular weight determination. This study produced statistical evidence of the behavior, in five different solvents, of representative compounds from each of the following chemical groups: hydrocarbons, alcohols, ketones, esters, ethers, acids, nitriles, amines, and sulfides. Analysis showed that acetone and ethyl acetate are the best solvents if the composition of the sample is not known. Chloroform proved to be a good solvent except for samples in which hydrogen bonding could occur. n-Heptane was satisfactory for six of the eight types of compounds; benzene war. by far the poorest solvent