Gas chromatographic and mass spectrometric analysis of the products of methylation of sulfonylurea drugs

Gas chromatographic analysis of the products of reaction of diazomethane with tolbutamide and chlorpropamide indicates the formation of three compounds in both cases. As expected, N-methylation (at sulfonamide nitrogen) is the predominant reaction; minor amounts of O-methylated product are also observed. The third product in both cases is the N-methylsulfonamide formed by decomposition of the N-methylated sulfonylurea during gas chromatography. Electron impact and chemulfonylurea during gas chromatography. Electron impact and chemical ionization mass spectrometric analysis, as well as 1H nuclear magnetic resonance examination of samples collected from gas chromatography, confirm the structural assignments. Additionally, proton magnetic resonance analysis of the crude reaction products established that N-methylsulfonamides are not formed in the course of the diazomethane reaction and that the O-methylated derivatives are true products of the reaction. The use of a paramagnetic shift reagent allowed direct estimation of the ratios of N- to O-methylation, and the demonstration that these ratios are not vitiated during gas chromatographic analysis.     

Sulfonylamido derivatives of 2-aminophenoxathiin-10,10-dioxide and related compounds possess antifungal action due to the possible inhibition of lanosterol-14-alpha-demethylase

Aryl/alkyl-sulfonylamido-, arylsulfenylamido-, arylcarboxamido-, and ureido/thioureido derivatives of 2-aminophenoxathiin-10,10-dioxide were prepared by reaction with sulfonyl/sulfenyl halides, sulfonic acid anhydrides, acyl chlorides, tosyl isocyanate, aryl/allyl isocyanates or isothiocyanates. Some of these derivatives, containing free amino groups, were further derivatized by reaction with 2,4,6-trisubstituted-pyrylium salts, aryl/allyl isocyanate/isothiocyanates or tosyl isocyanate. Several of the newly synthesized compounds act as effective antifungal agents against Aspergillus and Candida spp., some of them showing activities comparable to ketoconazole, with minimum inhibitory concentrations in the range of 0.3-0.5 microgram/mL. Their mechanism of antifungal action is hypothesized to be due to inhibition of lanosterol-14-alpha-demethylase.     

Sensitivity of mitochondrial peptidyl-prolyl cis-trans isomerase, pyridine nucleotide hydrolysis and Ca2+ release to cyclosporine A and related compounds

Prooxidants activate a specific Ca2+ release pathway from mitochondria. Here we investigate the inhibitory potency of cyclosporine A and six related compounds with respect to peptidyl-prolyl cis-trans isomerase (PPIase), pyridine nucleotide hydrolysis and Ca2+ release. Whereas the absolute inhibitory potency of the compounds varies by about three orders of magnitude, a given compound is always most effective on PPIase, followed by pyridine nucleotide hydrolysis, and least effective in Ca2+ release inhibition. The data show that pyridine nucleotide hydrolysis is a prerequisite but not a consequence of Ca2+ release. They also strongly suggest that PPIase participates in the Ca2+ release mechanism from intact mitochondria by regulating the intramitochondrial NAD+ glycohydrolase, and thereby ascribe a physiological function to the protein. Furthermore, a complete lack of correlation between the inhibitory potencies described here and the reported immunosuppressive activities of the drugs is evident.     

Chemical and phase transformations in the reduction and carbidizing of tungsten-cobalt compounds. II. X-ray phase analysis of the products of reduction and carbidizing of complex tungsten-cobalt oxide systems

Translated from Poroshkovaya Metallurgiya, No. 6(330), pp. 33–36, June, 1990.     

Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part I: Synthesis and biological activities of 3-(benzothiazol-2-yl)thiocephalosporin derivatives, CP0467 and related compounds

Insertional mutagenesis in transgenic mice is a powerful method to study structure/function relationships between individual genes and complex developmental traits in the whole organism. Unlike spontaneous or chemical-induced mutations, insertional mutations have the advantage that the mutant locus is "tagged" with the transgene and, therefore, readily accessible at the molecular level. Starting with the work on the limb deformity locus, we describe here the characterization of several mouse mutants generated by insertional mutagenesis with the pronuclear microinjection procedure. These transgenic lines have proven to be ideal as models for human disease and for studying the function of novel genes during development. We also describe the unique features of insertional mutations that arise in transgenic mice produced with the pronuclear microinjection procedure and provide recommendations on how to clone and characterize these mutations at the molecular level. Finally, we discuss future prospects for the use of this unique form of germline mutagenesis in the mouse.     

Evidence that the cannabinoid CB1 receptor is a 2-arachidonoylglycerol receptor. Structure-activity relationship of 2-arachidonoylglycerol, ether-linked analogues, and related compounds

An endogenous cannabimimetic molecule, 2-arachidonoylglycerol, induces a rapid, transient increase in intracellular free Ca2+ concentrations in NG108-15 cells through a cannabinoid CB1 receptor-dependent mechanism. We examined the activities of 24 relevant compounds (2-arachidonoylglycerol, its structural analogues, and several synthetic cannabinoids). We found that 2-arachidonoylglycerol is the most potent compound examined so far: its activity was detectable from as low as 0.3 nM, and the maximal response induced by 2-arachidonoylglycerol exceeded the responses induced by others. Activities of HU-210 and CP55940, potent cannabinoid receptor agonists, were also detectable from as low as 0.3 nM, whereas the maximal responses induced by these compounds were low compared with 2-arachidonoylglycerol. Anandamide was also found to act as a partial agonist in this assay system. We confirmed that free arachidonic acid failed to elicit a response. Furthermore, we found that a metabolically stable ether-linked analogue of 2-arachidonoylglycerol possesses appreciable agonistic activity, although its activity was apparently lower than that of 2-arachidonoylglycerol. We also confirmed that pretreating cells with various cannabinoid receptor agonists nullified the response induced by 2-arachidonoylglycerol, whereas pretreating cells with other neurotransmitters or neuromodulators did not affect the response. These results strongly suggested that the cannabinoid CB1 receptor is originally a 2-arachidonoylglycerol receptor, and 2-arachidonoylglycerol is the intrinsic physiological ligand for the cannabinoid CB1 receptor.     

Phylogenetic analysis of the core histones H2A, H2B, H3, and H4

The class I cytokine receptors consist of multiple subunits without any intrinsic enzymatic activities. Receptors for a subset of cytokines with overlapping biological activities often share a common receptor subunit with a signaling function. Each receptor regulates its specific signaling pathways, as well as common pathways depending on the target cell type.     

Inhibition of the mutagenicity of 2-nitrofluorene, 3-nitrofluoranthene and 1-nitropyrene by vitamins, porphyrins and related compounds, and vegetable and fruit juices and solvent extracts

When 21 vitamins including related compounds haemin, chlorophyllin, chlorophyll, biliverdin and bilirubin, as well as juices from five fruits and 25 vegetables and solvent extracts from the residues of fruits and vegetables were tested for their antimutagenic potencies with respect to mutagenicity induced by 2-nitrofluorene (2-NF), 3-nitrofluoranthene (3-NFA) and 1-nitropyrene(1-NP) in Salmonella typhimurium TA98 the following results were obtained. The tetracyclic nitroarenes 3-NFA and 1-NP were in general more effectively antagonized by potent antimutagenic compounds than the tricyclic 2-NF. beta-Carotene, retinol, retinal, retinoic acid, retinol palmitate, riboflavin 5'-phosphate, alpha-tocopherol, vitamins B12, C, K1 and K3 as well as biliverdin, bilirubin, chlorophyll, chlorophyllin and haemin exerted antimutagenicity against the nitroarenes cited previously. All other vitamins were inactive. While part of the juices were inactive, juices from cauliflower, carrots, chives, radishes and spinach exerted weak antimutagenic activities. However, weak to moderate co-mutagenic effects were seen with grapes, kiwi, pineapple, eggplant, celeriac, chicory greens, fennel leaves and radishes and strong effects with peppers which were not caused by the presence of growth-promoting factors. Most solvent fractions were inactive but fractions containing chlorophyll exerted antimutagenicity.     

Structure,strength, and wear resistance of materials of the system B4C-Al2O3

Translated from Poroshkovaya Metallurgiya, No. 6(318), pp. 89–95, June, 1989.     

Novel cephalosporin derivatives possessing a bicyclic heterocycle at the 3-position. Part II: Synthesis and antibacterial activity of 3-(5-methylthiazolo[4,5-c]pyridinium-2-yl)-thiomethylcephalosporin derivatives and related compounds

A series of cephalosporin derivatives with a thiazolopyridinium group at the 3-position was synthesized and evaluated for antibacterial activity. Some of these cephalosporin derivatives having a (5-alkylthiazolo[4,5-c]pyridinium-2-yl)thiomethyl group at the 3-position showed strong activity against Gram-positive and Gram-negative bacteria, including Pseudomonas aeruginosa. Among them, 5a showed a good antibacterial spectrum in vitro, and also showed a similar or slightly superior activity to that of ceftazidime in vivo against P. aeruginosa.     

Influence of getter and gas atmosphere on the reduction kinetics of γ-Fe2O3, and on the phase composition and particle size of the reaction products

The kinetic features and mechanism of reduction of γ-Fe₂O₃ in hydrogen in the presence of CaO as a getter for the gaseous reaction products was studied. Data were obtained on the kinetic constants, reaction rate, and evolution of surface area during the reaction. It was established that the getter has a favorable effect on the degree of dispersion of the reaction products.     

Mutational analysis of the role of the distal histidine and glutamine residues of prostaglandin-endoperoxide synthase-2 in peroxidase catalysis, hydroperoxide reduction, and cyclooxygenase activation

Site-directed mutants of prostaglandin-endoperoxide synthase-2 (PGHS-2) with changes in the peroxidase active site were prepared by mutagenesis, expressed in Sf-9 cells, and purified to homogeneity. The distal histidine, His193, was mutated to alanine and the distal glutamine, Gln189, was changed to asparagine, valine, and arginine. The guaiacol peroxidase activities of H193A, Q189V, and Q189R were drastically reduced to levels observed in the absence of protein; only Q189N retained wild-type PGHS-2 (wtPGHS-2) activity. The mechanism of hydroperoxide reduction by the PGHS-2 mutants was investigated using 15-hydroperoxyeicosatetraenoic acid (15-HPETE), a diagnostic probe of hydroperoxide reduction pathways. The hydroperoxide reduction activity of Q189V and Q189R was reduced to that of free Fe(III) protoporphyrin IX levels, whereas Q189N catalyzed more reduction events than wtPGHS-2. The percentage of two-electron reduction events was identical for wtPGHS-2 and Q189N. The number of hydroperoxide reductions catalyzed by H193A was reduced to approximately 60% of wtPGHS-2 activity, but the majority of products were the one-electron reduction products, 15-KETE and epoxyalcohols. Thus, mutation of the distal histidine to alanine leads to a change in the mechanism of hydroperoxide reduction. Reaction of wtPGHS-2, Q189N, and H193A with varying concentrations of 15-HPETE revealed a change in product profile that suggests that 15-HPETE can compete with the reducing substrate for oxidation by the peroxidase higher oxidation state, compound I. The ability of the PGHS-2 proteins to catalyze two-electron hydroperoxide reduction correlated with the activation of cyclooxygenase activity. The reduced ability of H193A to catalyze two-electron hydroperoxide reduction resulted in a substantial lag phase in the cyclooxygenase assay. The addition of 2-methylimidazole chemically reconstituted the two-electron hydroperoxide reduction activity of H193A and abolished the cyclooxygenase lag phase. These observations are consistent with the involvement of the two-electron oxidized peroxidase intermediate, compound I, as the mediator of the activation of the cyclooxygenase of PGHS.     

武钢4#高炉布料齿轮箱在线状态监测与分析诊断系统

介绍齿轮箱在线工况监测与故障分析诊断系统的设计思路，基本构成以及主要功能。系统采用工业控制计算机实现齿轮箱工况的不间断连续监测，并应用于炼铁高炉布料器齿轮箱的工况在线监测与分析诊断。提出了综合应用齿轮箱振动信息以及电机电流进行分析诊断的方法，为低速齿轮箱的故障诊断提供了一条可行的途径。