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Treatment of N-alkyl derivatives of 3,6-dichlorophthalimide and 4,5-dichlorophthalimide with potassium nitrite gave 3-hydroxy-6-nitro- and 4-hydroxy-5-nitrophthalimides. The potassium salts of these phenols were alkylated by dialkyl sulfates. The products were reduced to the 3-amino-6-alkoxy- and 4-amino-5-alkoxyphthalimides, and the fluorescence emission spectra of these products were measured. Hydrazinolysis of the phthalimides in a toluene medium gave phthalhydrazides. The luminescence spectra of several aminophthalhydrazides were measured. The infrared and proton magnetic resonance spectra of these and of some nitrophthalhydrazides were measured and aspects of these spectra characteristic of phthalhydrazides were identified.

Background: Platelet activation by platelet activating factor (PAF) seems to be involved in the inflammatory process in asthma and may serve as a possible target for the antiinflammatory drug nedocromil sodium, which is known to inhibit cell activation by different stimuli. Methods: We investigated the effect and the mode of action of nedocromil sodium on platelet activation by PAF. In a set of healthy volunteers ( n = 45) we investigated seven different parameters of platelet activation by PAF, thrombin, and Ca 2+ -ionophore. Results: Nedocromil sodium inhibited: (1) PAF-induced "shape change" reaction up to 78% (50% inhibitory concentration [IC 50 ]: 3 × 10 −9 mol/L), thrombin-mediated "shape change" up to 80% (IC 50 : 2 × 10 −8 mol/L), but not the Ca 2+ -ionophore-dependent reaction, (2) platelet aggregation by PAF up to 85% (IC 50 : 2 × 10 −9 mol/L); (3) release of thromboxane B 2 up to 82% (IC 50 : 5 × 10 −9 mol/L); (4) formation of inositol 1,4,5-triphosphate by PAF (IC 50 3 × 10 −7 mol/L), by thrombin (IC 50 : 1 × 10 −9 mol/L), but not by Ca 2+ ionophore; (5) increase of intracellular free calcium (IC 50 : 4 × 10 −7 mol/L); (6) formation of diacylglycerol (IC 50 : 9 × 10 −9 mol/L), and (7) translocation of protein kinase C (IC 50 : 1 × 10 −9 mol/L). Conclusions: In the concentration range of the IC 50 values found in these experiments, nedocromil sodium reduced PAF binding to platelets by only 10% to 20%, such that this interference cannot explain the observed effects of the compound. Inhibition of receptor-mediated platelet activation at an early stage in the signal transduction pathway, and without effect on Ca 2+ -ionophore-—induced platelet activation, suggests an action of nedocromil sodium at the level of the cell membrane.

18-Crown-6 and dicyclohexano-18-crown-6 complexes of potassium 2- and 4-nitrophenoxide, and 18-crown-6 complexes of thallium(I) 2- and 4-nitrophenoxide have been synthesized. Solvent effects on the visible spectra of the nitrophenoxide anions are independent of the nature of the cation and the nature of the complexing agent. The 18-crown-6 complex of thallium(I) 2-nitrophenoxide is a 1:2 complex. All the other complexes are 1:1. X-ray crystallographic examination of the potassium dicyclohexano-18-crown-6 complexes showed the potassium ion is octacoordinated in the 2-nitrophenoxide and heptacoordinated in the 4-nitrophenoxide.

The plausible role that platelet-derived growth factor (PDGF) has in the localized pathophysiological changes that occur in the arterial wall during development of atherosclerotic lesions led us to investigate the influence of recombinant (r)PDGF isomers -AA, -AB, and -BB on the expression of low density lipoprotein receptor (LDL-R) and 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase [(S)-mevalonate:NAD+ oxidoreductase (CoA-acylating), EC 1.1.1.88] genes. In addition, we clarified the role of protein kinase C (PKC) in expression of the two genes in human skin fibroblasts and vascular smooth muscle cells. The various rPDGF isoforms are distinct in their ability to activate transcription of both genes: (i) Both rPDGF-AA and -BB stimulate transcription of the LDL-R gene; in contrast, rPDGF-BB, but not -AA, activates transcription of the HMG-CoA reductase gene. (ii) All recombinant isoforms of PDGF activate transcription of the c-fos gene. (iii) While rPDGF-dependent transcription of the LDL-R gene occurs independently of PKC, transcription of the HMG-CoA reductase gene appears to involve the action of that enzyme.

Photolysis at 254 nm of alkyl benzohydroxamates [C 6 H 5 CONHOR: R=CH 3 , CH 2 CH 3 , CH(CH 3 ) 2 , CH 2 C 6 H 5 , CH(CH 3 )C 2 H 5 , CH(CH 3 )-n-C 6 H 13 ] in acetonitrile or hydrocarbon solvents gives benzamide. These reactions can be sensitized by benzophenone (at ca. 350 nm) and are quenched by cis-piperylene. Racemization occurred when 2-octyl (+)-benzohydroxamate was irradiated in cyclohexane. These results are consistent with a mechanism involving a triplet biradical. Photolysis of phenyl benzohydroxamate [C 6 H 5 CONHOC 6 H 5 ] and benzyl N-methylbenzohydroxamate [C 6 H 5 CON-(CH 3 )OCH 2 C 6 H 5 ] cannot be quenched with cis-piperylene and appear to be singlet reactions

The effects of nebulized platelet-activating factor (PAF) on the pulmonary and cardiovascular systems, and on the platelets present in peripheral blood were investigated in 9 normal individuals and in 6 patients with asthma and 3 individuals with lyso-PAF. The inhalation of PAF caused an acute decrease in specific airway conductance. The circulatory system parameters monitored showed an increase in heart rate while blood pressure decreased in both groups that were studied. The inhalation of PAF led to a significant increase in the differential count of polymorphonuclear leukocytes after 15 min; the count returned to the initial level after 24 h. However, the platelet count remained unchanged. The phosphatidylinositol (PI) turnover and in particular the formation of 1,4,5-inositoltrisphosphate (IP3) in platelets were investigated after PAF inhalation. It also mediated an increase in intracellular free calcium concentration, [Ca2+]i, in response to a second challenge with exogenous PAF. The basal levels of IP3 and [Ca2+]i were significantly greater in the platelets of patients with asthma than in those of normal individuals (p less than 0.01). Platelets that had been isolated from normal and asthmatic subjects had a higher concentration of IP3 and [Ca2+]i in the platelets after an in vitro exposure to PAF. After an inhalation challenge with PAF, the platelets of both the normal individuals and the patients with asthma showed a specific refractoriness to the in vitro exposure to PAF. Perhaps, this is an explanation for the PAF-dependent tachyphylaxis that is commonly observed in both normal and asthmatic individuals.(ABSTRACT TRUNCATED AT 250 WORDS)

N-Substituted 4,5-dichlorophthalimides react with potassium nitrite in refluxing dimethylformamide to form N-substituted 4-hydroxy- 5-nitrophthalimides

The effects of Ca(2+)-channel blockers (amlodipine, nifedipine, nitrendipine, and verapamil) on expression of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase (EC 1.1.1.88) and low density lipoprotein receptor (LDL-R) genes stimulated by recombinant platelet-derived growth factor BB isomer (PDGF-BB) were evaluated in human skin fibroblasts. The drugs enhanced expression of the LDL-R protein on the plasma membrane of the cells; in contrast, they inhibited expression of the HMG-CoA reductase gene. In addition, PDGF-BB-dependent stimulation of transcription of c-fos mRNA was inhibited also by the Ca(2+)-channel blockers. We conclude that PDGF-BB-dependent activation of the two genes is inhibited effectively by the Ca(2+)-channel blockers, at therapeutic concentrations, although they are unable to lower systemic cholesterol levels at these concentrations; however, they do modify responses of the two genes that are involved crucially in regulation of cellular cholesterol homeostasis.

Le moment dipolaire de 6 imides cycliques non substituees et de 3 N-methylimides a ete determine, en solution par la methode de Guggenheim-Smith. Les resultats sont compares a ceux obtenus par la methode Halverstadt-Kumler

Dipole moments of 12-crown-4, 15-crown-5 and 18-crown-6 have been measured for solutions in benzene and in cyclohexane at 15, 20, 25, and 30°, using the Guggenheim-Smith method. The dipole moments of the more common conformers of these crown ethers have also been calculated. The results indicate that these crown ethers exist in solution as mixtures of conformers. The conformational equilibria shift toward the more polar conformers as temperature increases. There is evidence that the more polar conformers of 12-crown-4 and 15-crown-5 are somewhat more favored in benzene solution than in cyclohexane, possibly as the result of a weak complexation with the former solvent.

Human platelet-derived growth factor (PDGF) is mainly composed of two polypeptide chains (PDGF-AB). All three possible dimeric forms of PDGF--i.e., PDGF-AA, PDGF-BB and PDGF-AB--exist in nature. We have used two recombinant PDGF homodimers to determine the roles of each isoform in the activation of phosphatidylinositol turnover in vascular smooth muscle cells (VSMC) isolated from rat thoracic aorta, their mitogenic effect on VSMC, and their vasoconstrictor effect on intact strips of aortic vascular tissue. Three Ca2+-channel blockers, nifedipine, verapamil, and diltiazem, were used as antagonists for investigating the PDGF-dependent changes mediated by the homodimers. PDGF-BB had a greater efficacy than PDGF-AA on inositol 1,4,5-trisphosphate release, on the formation of diacylglycerol, and on Ca2+ mobilization, which was also associated with vasoconstrictor activity and effective mitogenicity. PDGF-AA, on the other hand, was more potent than PDGF-BB in stimulating protein kinase C. In all instances, the activation of the phosphatidylinositol turnover by the two homodimers was inhibited by the Ca2+-channel blockers.

The first crystal structure of a potassium cation complex with dicyclohexano-18-crown-6 is reported. The potassium 2-nitrophenoxide complex ofsyn-cis-syn dicyclohexano-18-crown-6 crystallizes in the triclinic space group P\(\bar 1\) with cell constantsa=8.604(2),b=10.772(4),C=16.123(5)A, α=73.86(3)°,β=77.61(3)°, γ=82.68(3)° andZ=2 forDc=1.31 g cm−3. Least-squares refinement based on 2742 observed reflections led to a final conventionalR value of 0.040. Dicyclohexano-18-crown-6 has the shape of a saddle with the potassium cation sitting at the saddlepoint. The structure of the 2-nitrophenoxide anion is dominanted by the quinoid resonance contributor. Because the complex is devoid of significant intercomplex interactions, it is a prototypical 1:1:1 complex.

A radiotracer method to measure the solubility of thallium crown ether complexes is reported. Tl-204 is used as the radiotracer. The method is capable of a precision of 1% or better. The solubilities of 18-crown-6-bis-/thallium-o-nitrophenoxide/ in acetonitrile, benzene, chloroform and DMF were measured.

The ultraviolet absorption, fluorescence, and infrared absorption spectra of fifteen 3-benz-amidophthalimides are described. In general, the nature or position of the substituents on the benzamide moiety has little effect on the ultraviolet absorption and fluorescence spectra of these, compounds. The absorption baud at 271 nm is more sensitive to substituent variations than the other two bands (at 227 nm and 341 nm), indicating this band is a composite of bands observed in the spectra of 3-aminophthalimide and the substituted benzamide. The fluorescence of 3-amino-phthalirnide and the 3-benzamidophthalimides is due to the same transitions. The infrared absorption wavenumbers for the amide and imide vibrations of the 3-benzamidophthalimides are characterized.

Condensation of two equivalents of an aromatic cyclic anhydride with an aromatic diamine, or of two equivalents of an aromatic amine with an aromatic bisanhydride, results in the formation of an aromatic bisimide. Thirty-one such bisimides were prepared. The bisimides in which the two imide groups arc connected by a fully coplanar system show extremely low solubilities and high melting and decomposition temperatures. Many are also strongly colored. It is suggested that these properties may result from intermolecular charge-transfer effects in the solid slate, giving charge-transfer polymers.

The hydroxy- and methoxyphthalimidoacetic acids and the methyl methoxyphthalimidoacetates have been synthesized. The ultraviolet absorption spectra of these compounds in 95% ethanol, aqueous acid, and aqueous base are discussed. Structures are suggested for the hydroxy- and methoxyphthalamate ions which are formed in basic solution. The Gabriel-Colman rearrangements of methyl 3- and 4 - methoxyphthalimidoacetate give, respectively, 8-methoxy-4-hydroxy-3 - carbomethoxy-1(2H)-isoquinolone (VII) and 6-methoxy-4-hydroxy-3-carbomethoxy-1(2H)-isoquinolone (VIII).

The ultraviolet absorption spectra of aqueous and alcoholic solutions of the pyridinemono-carboxylic acids and amides, of the vicinal pyridinedicarboxylic acids, and of the 1-oxides of these compounds, were measured and qualitatively interpreted. The photolysis of the 1-oxides in aqueous solution resulted principally in their deoxygenation. Photolysis of picolinamide 1-oxide also gave a rearrangement product, 1-formyl-2-pyrrolecarboxamide. The photolyses of the 2- and 4-monosubstituted 1-oxides were somewhat faster than those of the 3-substituted 1-oxides. The experimental results are discussed in terms of possible hydrogen-bonding effects.

Treatment of methyl 4-nitrophthalimidoacetate (I) with sodium methoxide in refluxing methanol results in a Gabriel-Colman rearrangement to give 7 - nitro-4-hydroxy-3-carbomethoxy-1(2H) - isoquinolone (II). Under the same conditions, N-substituted 3-nitrophthalimides (IV) yield N-substituted 3-methoxyphthalimides (V).

Dipole moments of 12-crown-4, 15-crown-5 and 18-crown-6 have been measured for solutions in benzene and in cyclohexane at 15, 20, 25, and 30°, using the Guggenheim-Smith method. The dipole moments of the more common conformers of these crown ethers have also been calculated. The results indicate that these crown ethers exist in solution as mixtures of conformers. The conformational equilibria shift toward the more polar conformers as temperature increases. There is evidence that the more polar conformers of 12-crown-4 and 15-crown-5 are somewhat more favored in benzene solution than in cyclohexane, possibly as the result of a weak complexation with the former solvent.

A monoclonal antibody is described which reacts with the intermediate filament proteins vimentin, desmin, keratins, actin, and myosin. This is the first report of an epitope common to intermediate filament proteins and myosin. X1, the wide-spectrum monoclonal antibody in question, was isolated in the course of screening monoclonal antibodies to chicken thymocytes. Cross-reactivities were investigated by immunofluorescence on various types of cultured cells and sectioned tissues, ELISA with a panel of purified antigens, immunoprecipitation, immunodot tests, and immunoblotting.

A RECENT paper (3) described the preparation and some of the properties of the nitrophthaloyl and aminophthaloyl derivatives of glycine. This work has been extended to the preparation of the nitrophthaloyl and aminophthaloyl derivatives of a number of other amino acids. Although it gives excellent results with glycine, the use of nitrobenzene as a solvent for nitrophthaloylations was unsatisfactory with other amino acids. The phthaloylation method of Billman and Harting (2) gave satisfactory nitrophthaloylations in most cases. The nitrophthalic acids were as effective as their anhydrides in achieving nitrophthaloylation by this method. The aminophthaloyl derivatives were prepared by hydrogenation of the nitrophthaloyl derivatives.