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Chemical investigation of the Australian rainforest plant Doryphora sassafras has resulted in the isolation of a new natural product, 2-methyl-1-(p-methoxybenzyl)-6,7-methylenedioxyisoquinolinium chloride (1). The iodide salt of compound 1 has previously been synthesized but only partially characterized. This paper reports the full spectroscopic characterization of 1 by MS, IR, UV, and NMR data.
The effect of a surface water layer on DNA strands deposited on a substrate was studied by atomic force microscopy (AFM). DNA molecules were deposited and stretched on chemically modified glass coverslips by a molecular combing method. Lambda bacteriophage DNA molecules were aligned on the organosilane-modified substrate surfaces by chemical and physical adsorption during the molecular combing. The combed DNA molecules were observed in humidity-controlled air and in aqueous solutions by pulsed-force-mode AFM (PFM-AFM). Chemical modification of cantilevers with an Au-coated tip by organothiol compounds was also applied to DNA observation. Mapping adhesive forces in aqueous media was useful to discriminate chemically the DNA strands from the substrate surface. The results suggest that PFM-AFM can be used widely to image the stretched DNA molecules on the silane-modified substrates.
The morphological changes produced by four series of organic trypanocidal drugs have been studied by quantitative and by qualitative methods using phase-contrast and fluorescence microscopy. Basic drugs were absorbed rapidly into the region of the kinetoplast; acidic drugs did not affect this region. Faint granules, which were present in some trypanosomes before the administration of drugs, absorbed the drugs and increased in contrast relative to the cytoplasm. Hydroxystilbamidine, quinapyramine, related compounds, and possibly also suramin produced additional granules which did not contain drug. These additional granules are similar to the granules (volutin granules) which occur in trypanosome infections (not treated with drugs) when trypanosomes are about to be cleared from the blood. Homidium did not produce additional granules.
Continuous cultivation of the bovine hemoparasites Babesia bovis and Babesia bigemina was developed as an in vitro microtest to assess parasite susceptibility to babesicidal compounds. Reproducibility of parasite multiplication rates was independent of culture size, making it possible to use a microscale of 100 microliters for each test sample. Inhibitory concentrations (IC50s) of a commonly used babesicide, quinuronium sulfate, evaluated by this in vitro method were found to be 5 x 10(-8) g/ml for B. bovis and 2 x 10(-9) g/ml for B. bigemina.
Reaction of 1-methylquinolinium-2-dithioacetic acid zwitterions with excess methyl iodide in dimethylformamide gave the corresponding bis(2-methylthio)vinyl derivatives. These compounds were more soluble in both aqueous and organic media than the dithioacetic acid zwitterions but showed comparable antileukemic activity in mice. Reaction with morpholine converted a bis(2-methylthio)vinyl derivative almost quantitatively to the 2-mono(methylthio)-2-morpholino derivative. Leukemia cell culture studies of the 6-methyl derivative showed no effect on cell cycle processes.
The novel K+ channel blocker 6,10-diaza-3(1,3)8,(1,4)-dibenzena-1,5(1,4)-diquinolinacy clodecaphane (UCL 1684) has been tested for its ability to inhibit Ca2+ -activated K+ currents in cultured rat chromaffin cells. Low nanomolar concentrations of UCL 1684 produced a rapid and reversible inhibition of the slow, apamin-sensitive, tail current activated by a depolarizing voltage command. This compound also inhibited the muscarine activated outward current with an IC50 of 6 nM. These results confirm UCL 1684 to be the most potent non-peptidic blocker of the apamin-sensitive Ca2+ -activated K+ channel so far described.
The most common mutation in the gene associated with cystic fibrosis (CF) causes deletion of phenylalanine at residue 508 (delta F508) of the gene product called CFTR. This mutation results in the synthesis of a variant CFTR protein that is defective in its ability to traffic to the plasma membrane. Because earlier studies showed delta F508-CFTR retains significant phosphorylation-regulated chloride (Cl-) channel activity, processes capable of restoring the mislocalized delta F508-CFTR to the correct cellular destination may have therapeutic benefit. Here we report one such process that involves overexpression of the mutant protein and appears to result in the escape of a small amount of delta F508-CFTR to the plasma membrane. In recombinant cells where expression of delta F508-CFTR is controlled by the metallothionein promoter, this effect can be brought about by treatment with sodium butyrate. Although cAMP-activated Cl- channel activity could also be detected in immortalized human airway epithelial cells homozygous for the delta F508 mutation at the single cell level, treatment with butyrate did not generate a measurable cAMP-stimulated Cl- current in polarized monolayers of primary CF airway epithelia. However, the observation that overexpression can effect the presence of recombinant delta F508-CFTR at the plasma membrane suggests that perhaps other butyrate-like compounds that are more potent and more specific for the promoter of the CF gene may be efficacious in alleviating the Cl- channel defect associated with CF.
Thirteen alkaloids, hernandezine, thalidezine, N-desmethylthalidezine, isothalidezine, thalistyline, thalistyline methodiiodide, N-desemethylthalistyline, berberine, columbamine, jatrorrhizine, palmatine, thalifendine, magnoflorine and the artifact, 8-trichloromethyldihydroberberine were isolated from the roots of Thalictrum podocarpum Humb. In addition, oxyberberine and thaliglucinone were obtained in very minor amounts and identified by tlc. Of these compounds, N-desmethylthalidezine and isothalidezine are new bisbenzylisoquinoline alkaloids. Sucrose was isolated from the alcoholic extract. Hernandezine, thalistyline, thalidezine, thalistyline methodiiodide and N-desmethylthalistyline were found to possess antimicrobial activity against Mycobacterium smegmatis at concentrations of 100 microgram/ml or less.
Platelet activating factor (PAF) is ubiquitous in mammals, and may have multiple functions in the central nervous system. Triazolobenzodiazepine compounds are active both at the GABAA receptor and as PAF antagonists. To investigate whether PAF antagonist activity is involved in the actions of triazolobenzodiazepines, we examined effects of two non-benzodiazepine PAF antagonists on binding and function at the GABAA receptor. The gingkolide terpene, BN 52021 and the dioxolane-based compound BN 52115 had no effect on benzodiazepine binding or chloride channel binding in cortical membrane preparations. However, chloride uptake into cortical synaptoneurosomes was enhanced with 1 microM BN 52021 but not 1 microM BN 52115. The effect of BN 52021 was prevented by 1 microM flumazenil. PAF antagonists appear to augment GABAA receptor function without affecting binding.
7-Dialkylamino- and 7-alkylsulfenyl-1-alkylquinolinium salts have been synthesized using a novel synthetic approach. The key intermediate, 7-fluoro-1-methylquinolinium iodide, was shown to possess high reactivity toward nitrogen and sulfur nucleophiles, and the kinetics of this nucleophilic aromatic substitution reaction was investigated. A wide variety of compounds were synthesized and characterized spectroscopically. High fluorescence quantum yields were observed, and this was attributed to the rigid molecular architecture. The thermal and photochemical stability of a number of compounds was investigated, and it was demonstrated that 7-dialkylamino-1-methylquinolinium salts have superior stability compared to a number of hemicyanine dyes and rigid charge-transfer probes. Based on the high quantum yields, the large Stokes shifts, and in particular, the high thermal and photochemical stability, it is concluded that 7-dialkylamino-1-methylquinolinium salts are excellent color-shifting, mobility-sensitive fluorescent probes for polymer characterization and other demanding applications.
Molecules of the title compound, C9H8NO+.Cl-.H2O, are linked into two rings by strong hydrogen bonding via the free water molecules and the Cl- anions. The two hydrogen-bonded rings are joined to give a corrugated chain along [001]. Comparisons with other 8-hydroxyquinoline-based salts are also presented, highlighting similar ring structures in a 1:1 salt with Kemp's triacid (r-1,c-3,c-5-trimethylcyclohexane-1,3,5-tricarboxylic acid) and in 8-hydroxy-1-methylquinolinium chloride monohydrate.
1. Our aim was to identify the small-conductance Ca(2+)-activated K(+) channel(s) (SK) underlying the apamin-sensitive afterhyperpolarization (AHP) in rat superior cervical ganglion (SCG) neurones. 2. Degenerate oligonucleotide primers designed to the putative calmodulin-binding domain conserved in all mammalian SK channel sequences were employed to detect SK DNA in a cDNA library from rat SCG. Only a single band, corresponding to a fragment of the rSK3 gene, was amplified. 3. Northern blot analysis employing a PCR-generated rSK3 fragment showed the presence of mRNA coding for SK3 in SCG as well in other rat peripheral tissues including adrenal gland and liver. 4. The same rSK3 fragment enabled the isolation of a full-length rSK3 cDNA from the library. Its sequence was closely similar to, but not identical with, that of the previously reported rSK3 gene. 5. Expression of the rSK3 gene in mammalian cell lines (CHO, HEK cells) caused the appearance of a K(+) conductance with SK channel properties. 6. The application of selective SK blocking agents (including apamin, scyllatoxin and newer non-peptidic compounds) showed these homomeric SK3 channels to have essentially the same pharmacological characteristics as the SCG afterhyperpolarization, but to differ from those of homomeric SK1 and SK2 channels. 7. Immunohistochemistry using a rSK3 antipeptide antibody revealed the presence of SK3 protein in the cell bodies and processes of cultured SCG neurones. 8. Taken together, these results identify SK3 as a major component of the SK channels responsible for the afterhyperpolarization of cultured rat SCG neurones.
Homidium, quinapyramine, and suramin (Group II compounds) produce their trypanocidal effect in vivo only after a latent period of 24 hr. or more, during which time the trypanosomes may continue to multiply; this is in contrast to trivalent arsenical and diamidine compounds (Group I compounds), which begin to act immediately. Group II compounds also differ from Group I compounds in that (a) they have only a slight tendency to combine with trypanosomes, (b) they have little trypanocidal action in vitro, but (c) they make trypanosomes non-infective to fresh subinoculated mice. To explain these features it is postulated that homidium, quinapyramine, and suramin first combine in small amounts with some receptor on the trypanosome and then block some biochemical system which produces a hypothetical substance X which is needed for cell division of the trypanosome; the trypanosome is supposed to contain a preformed store of this substance X sufficient for several divisions to take place; and it is only when this store is exhausted that cell division is prevented and the trypanosome eventually dies.
Two Trypanosoma simiae stocks were initiated in culture with tsetse-derived metacyclics. They were propagated axenically as trypomastigote forms at 35 degrees C in 4% CO2 in air. Populations of trypanosomes were incubated with various concentrations of antitrypanosomal compounds. Growth was monitored after 24 h of incubation and the growth inhibition was calculated. Diminazene aceturate, quinapyramine sulphate, DL-alpha-difluoromethylornithine, and Ro 15-0216 showed activity against the stocks. Suramin and Mel Cy showed little effect upon the growth of the parasite populations. Isometamidium chloride gave questionable results in the 24 h growth inhibition test, but the results of a long-term viability assay indicated some degree of drug resistance (or drug tolerance). The results obtained herein correlate with observations obtained from in vivo studies in pigs. It is thus concluded that in many cases the cryptic nature of T. simiae rather than drug resistance is responsible for the failure of chemotherapy of simiae-trypanosomiasis in pigs.
Dequalinium compounds are known as chemotherapeutic and bactericidal agents. They are used in various areas of medicine and oral medicine for combating cases of mixed infections. Until now, results of basic research studies have been published whose objective was to examine the suitability of dequalinium preparations as cleansing agents and intracanal dressings for endodontic use. This article presents for the first time a number of selected cases from a clinical research study in which widespread periapical lesions revealed before the start of treatment were treated with a preparation whose active ingredient was dequalinium acetate. The results of treatment and follow-up are given. These case reports show that healing of the periapical lesions occurs relatively quickly and is generally completed within a period of 9 months.
A series of isoquinolines, N-methyl-1,2-dihydroisoquinolines, N-methyl-1,2,3,4-tetrahydroisoquinolines, 1,2,3,4-tetrahydroisoquinolines, and N-methylisoquinolinium ions were tested as inhibitors of monoamine oxidases A and B. All compounds were found to act as reversible and time-independent MAO inhibitors, often with a distinct selectivity towards MAO-A. As a class, the N-methylisoquinolinium ions were found to be the most active MAO-A inhibitors, with N-methyl-6-methoxyisoquinolinium ion emerging as a potent (IC50 = 0.81 microM) and competitive MAO-A inhibitor. Comparative molecular field analysis (CoMFA, a 3D-QSAR method) of MAO-A inhibition was performed using the data reported here and in the literature. Using the steric and lipophilic fields of the inhibitors, quantitative models with reasonable predictive power were obtained that point to the importance of steric, lipophilic, and polar interactions in modulating MAO-A inhibitory activity.
The aim of this work was to characterise the intestinal absorption of organic cations, by testing the possibility of involvement of known members of the amphiphilic solute facilitator (ASF) family in this process. For that purpose, the characteristics of the uptake of 1-methyl-4-phenylpyridinium, a model organic cation, at the brush-border membrane of Caco-2 cells were compared with those of the extraneuronal monoamine transporter (EMT)-mediated transport. Uptake of [3H]MPP+ by Caco-2 and 293hEMT cells showed pH-dependence: it was significantly reduced (to 86% and 62% of control, respectively) when the pH of the extracellular medium was decreased to 6.2, and increased (to 116% and 136% of control, respectively) when the extracellular pH was increased to 8.2. Uptake of [3H]MPP+ by Caco-2 cells and 293hEMT cells showed potential-dependence: substitution of KCl for NaCl in the incubation medium resulted in a reduction in the inward transport of [3H]MPP+ (to 70% and 40% of control, respectively). Uptake of [3H]MPP+ by Caco-2 and 293hEMT cells showed only little dependence on Na+: substitution of NaCl of the incubation media with LiCl resulted in a small decrease (of 19% and 14%, respectively) in [3H]MPP+ uptake. However, when NaCl was substituted with choline chloride, a significant reduction in [3H]MPP+ uptake by Caco-2 and 2931hEMT cells (of 56% and 68%, respectively) was observed. The effect of various compounds on initial rates of [3H]MPP+ uptake into Caco-2 and 293hEMT cells was tested. All compounds tested interacted with the specific [3H]MPP+ uptake in both cell lines. There was no correlation between the IC50s in relation to inhibition of [3H]MPP+ uptake into Caco-2 cells and into 293hEMT cells. Reverse transcriptase-polymerase chain reaction indicates that mRNA of hEMT and of the human organic cation transporter 1 (hOCT1) are present in Caco-2 cells. In conclusion, our results suggest that uptake of organic cations at the brush-border membrane of Caco-2 cells may occur through two distinct Na+-independent transporters belonging to the ASF family: hEMT and hOCT1.
This study examined mechanisms of Cl- transport in rat lymphocytes under a variety of conditions. Basal intracellular Cl- concentration ([Cl-]i) was not different between cells assayed in the presence of HCO3- or its absence (HEPES). Removal of external Cl- resulted in a fall in [Cl-]i and a rapid rise in intracellular pH (pH(i)). Both Cl- efflux and the rise in pH(i) were blocked by DIDS or removal of external Na+ but were unaffected by furosemide. The mechanisms governing Cl- influx were assessed in cells that had been Cl- depleted for 1 h. Reexposure to Cl- resulted in a rapid rise in [Cl-]i that was partially inhibited by pretreatment with DIDS (57%) and partially inhibited by pretreatment with furosemide (45%). Pretreatment with both compounds together completely blocked Cl- influx. Cl- depletion caused a marked increase in pH(i) that rapidly declined toward normal when the cells were reexposed to Cl-. Preincubation with DIDS completely blocked this decrease in pH(i). In contrast, neither removal of Na+ nor preincubation with furosemide affected the decline in pH(i) when the cells were reexposed to Cl-. We conclude that, in thymic lymphocytes, Cl-/HCO3- (or Cl-/base exchange) regulates both Cl- influx and efflux. Cl- efflux is totally inhibited by DIDS and is mediated by a Na+-dependent Cl-/HCO3- exchanger. Cl- influx is partially DIDS sensitive and partially furosemide sensitive and is mediated by both a Na+-independent Cl-/HCO3- exchanger and by a Na+-K+-2Cl- cotransporter.