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At least 289 records · Page 16Linked to original sources
PubMed2005

Efforts directed toward the synthesis of colchicine: application of palladium-catalyzed siloxane cross-coupling methodology.

[reaction: see text] Colchicine is an important and synthetically challenging natural product. The key synthetic step in this approach to the synthesis of colchicine involved a palladium-catalyzed cross-coupling reaction between 5-bromotropolone (4) and an aryl siloxane to form the aryl-tropolone bond. The coupling of a variety of highly functionalized aryl siloxane derivatives was investigated and optimized coupling conditions were developed. It was discovered that a palladium catalyst with a high degree of phosphine ligand coordination (5 equiv of phosphine/mol Pd) was necessary to efficiently couple aryl siloxanes with 5-bromotropolone (4). In addition, the coupling approach has provided a direct comparison between siloxane and boronic acid coupling technologies that demonstrated that aryl siloxanes and boronic acids produce similar yields of highly functionalized biaryl products.

Bromus↗
PubMedDate not supplied

Determination of butyltin, cyclohexyltin and phenyltin compounds in beers and wines.

Butyl- cyclohexyl- and phenyltin compounds were extracted from enzymically-hydrolysed wine and beer samples with 0.05% tropolone in pentane. Methyl derivatives were made by Grignard reaction for determination by gas chromatography-atomic absorption spectrometry. Wine and beer samples contained less than 0.1 to 160 nl/ml of butyltins from an undetermined source of contamination. GC-MS confirmation of butyltins also detected phenyltin, and di- and tricyclohexyltin compounds at levels less than the GC-AAS based method detection limits of 0.05-0.13 ng Sn/mL.

Beer↗
PubMedDate not supplied

A method for the analysis of butyltin chlorides in air by gas chromatography with atomic emission detection.

An initial screening test compared the use of tropolone (2-hydroxy-2,4-6-cycloheptatrienone) in acetic acid with sodium diethyldithiocarbamate (NaDDC) as chelating agents for the extraction of butyltin chlorides from glass fiber filters and XAD-2 resin tube. NaDDC was chosen for subsequent analyses. Mono-, di-, and tributyltin chloride were spiked onto glass fiber filters and XAD-2 resin, extracted in toluene with NaDDC and derivatized with pentylmagnesium bromide. Derivatized butyltin species were determined by gas chromatography with plasma atomic emission detection. Glass fiber filters and XAD-2 resin were found to provide high retention of butyltin compounds during sampling and efficient recovery of butyltin compounds by extraction with NaDDC.

Air Pollutants, Occupational↗
PubMed2003

Antibacterial effect of beta-thujaplicin on staphylococci isolated from atopic dermatitis: relationship between changes in the number of viable bacterial cells and clinical improvement in an eczematous lesion of atopic dermatitis.

Beta-thujaplicin (hinokitiol) is a tropolone-related compound purified from the wood of Chamaecyparis obtusa, SIEB: et Zucc. and Thuja plicata D. Don. All Staphylococcus aureus isolates were inhibited by beta-thujaplicin with MICs of 1.56-3.13 mg/L. However, a paradoxical zone phenomenon occurred, with each isolate producing regrowth at higher beta-thujaplicin concentrations. Other antimicrobial agents showed a wide range of MICs. The combination of beta-thujaplicin and zinc oxide inhibited the paradoxical zone phenomenon, and enhanced killing activity against clinically isolated staphylococci. Large numbers of viable bacterial cells, especially S. aureus cells, were detected in the skin surface of atopic dermatitis, in comparison with those in healthy volunteers. The number of cells increased as the severity of the skin condition worsened. Topical application of beta-thujaplicin resulted in a reduction in the number of bacterial cells on the skin surface, and an improvement in skin condition after treatment. The results of this study suggest that the degree of reduction in the number of viable bacterial cells in an eczematous lesion of atopic dermatitis is related to the degree of improvement in skin condition.

Adolescent↗
PubMedDate not supplied

Emboli from an extraluminal blood flow hollow fiber oxygenator with and without an arterial filter during cardiopulmonary bypass in a pig model.

The effect of an arterial filter on visceral emboli was quantified with autologous indium-111 labeled platelets (INPLT) during cardiopulmonary bypass (CPB) in Yorkshire pigs. Biodistribution of INPLT was determined in 12 control pigs (30-35 kg, unoperated control [n = 6] and sham operated control [n = 6]). CPB was carried out with (n = 6) and without (n = 6) an arterial filter in 12 pigs at a flow rate of 2.5-3.5 L/min. Platelets labeled with In-111 tropolone (650-780 microCi) were injected intravenously 24 hr before CPB. All pigs were systemically heparinized (activated coagulation time > 400 sec); CPB was instituted with a roller pump, an extraluminal blood flow oxygenator (Bentley Univox, 1.8 m2), and an arterial filter (0.25 m2) and continued for 3 hr. Platelet kinetics, pooling, and counts were monitored by a Geiger probe and a Coulter counter. The thrombi in the oxygenator and arterial filter and emboli in viscera and brain were imaged with a gamma camera and measured with an ion chamber and gamma counter. Percentage of INPLT (mean +/- SD) in organs, tissues, and components of the circuit in four groups of pigs was calculated. Flow cytometry with antibodies to CD61 (GPIIIa) and CD62P (GMP-140: control) of porcine platelets was carried out with blood samples taken before, during, and after CPB for estimation of circulating platelet aggregates and platelet microparticles. Pulmonary, renal, cardiac, and cerebral emboli in pigs undergoing CPB with and without a filter were similar (p < 0.1). The amount of filter adherent thrombi was small (0.04 +/- 0.01%); oxygenator adherent thrombus in both groups was similar (p < 0.1). Emboli were found in the cerebral medulla, hippocampus, and posterior cerebral cortex in both groups. During CPB, the arterial filter functioned minimally as a trap for platelet thrombi detached from the oxygenator and circulating emboli. Flow cytometry of blood demonstrated the shift of equilibria from single platelets to platelet aggregates and microparticles during CPB and their gradual reversal to single platelets after CPB; the loosely adherent emboli disaggregated and further shifted these equilibria to single platelets and smaller aggregates, probably through the action of endogenous nitric oxide and prostacyclin. The emboli were trapped in organs and tissues and microparticles were sequestered by the reticuloendothelial system.

Animals↗
PubMed1988

Indium-111 labeled purified granulocytes in the diagnosis of synthetic vascular graft infection.

Indium-111 labeled leukocytes have been shown to be useful in the diagnosis of synthetic vascular graft infection. To minimize the potential effects of labeled red blood cells and platelets on image interpretation, the authors prepared purified autologous granulocytes (PG) from 84 ml of blood using Volex enhanced gravity sedimentation and Ficoll-Hypaque double density centrifugation. The labeling efficiency of PG with In-111 tropolone was 90 +/- 9% (mean +/- SD). Imaging was performed 18-24 hours following injection of approximately 445 microcuries of In-111 PG in 26 patients with suspected infection of vascular grafts that had been implanted 12 days to 12 years prior to the study. In ten patients with proven graft infection, seven had positive In-111 PG scans. Ten of 11 patients without infection had negative scans. In five patients with clinically equivocal findings, scan results were positive in one, negative in one, and equivocal in three. A false-positive scan occurred in a patient with an uninfected inflammatory pseudoaneurysm of an aortic graft. These results confirm an earlier report that In-111 PG imaging is a useful technique in the diagnosis of synthetic vascular graft infection.

Aged↗
PubMed1998

Interference of patient medication in the radiolabelling of white blood cells: an update.

Evidence is now accumulating that patient medication can adversely affect the radiolabelling of white cells. We have undertaken a survey for the years 1981-97 to examine instances of unusually low labelling efficiencies of 111In-tropolone and 99Tcm-HMPAO labelled white cells. Respondents were asked to ascertain which drugs were being taken on the day of the test. Fifty adverse reports were received during that period. Many patients were taking drugs which are known to affect white cell function, including cephalosporins, azathioprine, prednisolone, cyclophosphamide, nifedipine, suphasalazine, iron salts and heparin. Using Bradford-Hill's criteria to assess whether an association between two variables is also one of causation, it was found that there was a high probability that the above drugs caused the low labelling efficiencies.

Drug Interactions↗
PubMed1985

The kinetics of unmatched and HLA-matched 111in-labelled homologous platelets in recipients with chronic marrow hypoplasia and anti-platelet immunity.

The kinetics of homologous platelets, labelled in plasma with 111In-tropolonate, have been studied in five recipients with chronic marrow hypoplasia and severe thrombocytopenia, who were refractory to platelet transfusions as a result of alloimmunization. Mean platelet life span (MPLS), recovery, plasma 111In level and splenic and hepatic uptake kinetics were studied on two occasions, one using HLA-matched platelets and the other unmatched platelets. In each case, recovery of labelled platelets at 1 h post-injection and MPLS improved with HLA matching, although this improvement was highly variable. Only two of the five subjects would have derived any significant benefit from HLA-matched as compared with unmatched platelet transfusions. It was concluded that the need exists for additional cross-matching procedures, possibly related to platelet specific antigens, in patients who remain refractory to platelet transfusion.

Adolescent↗
PubMed1997

The mechanism of tubulin-colchicine recognition--a kinetic study of the binding of a bicyclic colchicine analogue with a minor modification of the A ring.

2-Methoxy-5-(2',3',4'-trimethoxy)-2,4,6-cycloheptatrien-1-one (MTC) is a colchicine analogue that lacks the B ring. 2-Methoxy-5-(2',4'-dimethoxyphenyl)-2,4,6-cycloheptatrien-1-one (MD) is an A-ring analogue of MTC, in which one methoxy group is replaced by a hydrogen atom. This paper describes the kinetic features of MDC binding to tubulin, and compares its behaviour with MTC to analyse the effect of the A-ring modification on the recognition process by tubulin. Binding is accompanied by a strong enhancement of MDC fluorescence and quenching of protein fluorescence. The kinetic and thermodynamic parameters were obtained from fluorescence stopped-flow measurements. The kinetics are described by a single exponential, indicating that this drug does not discriminate between the different tubulin isotypes. The observed pseudo-first-order rate constant of the fluorescence increase upon binding increases in a non-linear way, indicating that this ligand binds with a similar overall mechanism as colchicine and MTC, consisting of a fast initial binding of low affinity followed by a slower isomerisation step leading to full affinity. The K1 and k2 values for MDC at 25 degrees C were 540 +/- 65 M(-1) and 70 +/- 6 s(-1) respectively. From the temperature dependence, a reaction enthalpy change (deltaH(o)1) of the initial binding of 49 +/- 11 kJ/mol(-1) and an activation energy for the second step of 28 +/- 9 kJ/mol(-1) were calculated. Displacement experiments of bound MDC by MTC allowed the determination of a rate constant of reverse isomerisation of 0.60 +/- 0.07 s(-1) at 25 degrees C and the activation energy of 81 +/- 6 kJ/mol(-1). The overall binding constant was (6.3 +/- 0.2) x 10(4) M(-1) at 25 degrees C. Combination of these results with the kinetic parameters for association gives a full characterisation of the enthalpy pathway for the binding of MDC. The pathway of MDC is shown to differ considerably from that of MTC binding. Since its structural difference is located in ring A, this result indicates the use of ring A in the first step. The kinetics of the binding of MDC in the presence of some A-ring colchicine analogues (podophyllotoxin, 3',4',5'-trimethoxyacetophenone and N-acetylmescaline) and a C-ring analogue (tropolone methyl ether) suggest that the A and C rings are involved in the binding of MDC.

Animals↗
PubMed1985

Purification and kinetic mechanism of human brain soluble catechol-O-methyltransferase.

The soluble form of human brain catechol-O-methyltransferase (EC 2.1.1.6, COMT) has been purified approximately 4,000-fold from a 250,000 X g supernatant solution. The purified enzyme exhibits a molecular weight near 27,500 and a pI value equal to approximately pH 5.0. Initial velocity and product inhibition studies are consistent with an ordered reaction mechanism for soluble COMT. Tropolone, a dead-end inhibitor, exhibited a competitive pattern of inhibition when dopamine (DA) was the varied substrate and an uncompetitive pattern when S-adenosyl-L-methionine (SAM) was the varied substrate. These observations strongly suggest that the soluble form of COMT from human brain catalyzes the O-methylation of catecholamines via an ordered reaction mechanism in which SAM is the leading substrate. Since the membrane-bound form of COMT catalyzes the O-methylation of catecholamines through an identical reaction mechanism, these data provide further evidence that two forms of COMT, while being localized in distinct subcellular compartments, are quite similar in their molecular structure.

Brain↗
PubMed1987

Turnover of dopamine and dopamine metabolites in rat brain: comparison between striatum and substantia nigra.

Measurements of the turnover of dopamine (DA) and DA metabolites have been performed in the striatum and substantia nigra (SN) of the rat. Turnover rates of 3,4-dihydroxyphenylacetic acid (DOPAC) and homovanillic acid have been assessed from the disappearance rates after blocking their formation by inhibition of monoamine oxidase by pargyline and of catechol-O-methyltransferase by tropolone. DA turnover has been measured as 3-methoxytyramine (3-MT) plus DA accumulation rate after MAO inhibition by pargyline and as accumulation rate of 3,4-dihydroxyphenylalanine (DOPA) after inhibition of aromatic amino acid decarboxylase by NSD 1015 or NSD 1034. These measures of DA turnover have been compared with alpha-methyl-p-tyrosine (alpha-MT)-induced DA disappearance rate. In SN all the different measures of DA turnover are in the same range (55-62 nmol/g protein/h) whereas in striatum DOPA accumulation rate after NSD 1015 and alpha-MT-induced DA disappearance rate (16-23 nmol/g/h) are much lower than DOPAC disappearance rate after pargyline, 3-MT plus DA accumulation rate after pargyline, and DOPA accumulation rate after NSD 1034 (39-46 nmol/g/h). The data confirm our previous findings indicating that the fractional turnover rate of DA is more rapid in SN than in striatum and that O-methylation of DA is relatively more important in SN. In striatum at least two pools of DA with different turnover rates appear to exist, whereas in SN, DA behaves as if located in a single compartment.

3,4-Dihydroxyphenylacetic Acid↗
PubMed1994

Redistribution of granulocytes in patients after major surgical stress.

Major surgery induces a stress response characterized by granulocytosis in peripheral blood, and increased secretion of adrenaline and cortisol. The purpose of this study was to investigate the redistribution of granulocytes in response to major surgical stress. Granulocytes were isolated from eight surgical patients and eight healthy volunteers, labelled with Indium-111-tropolone, and reinjected. The distribution of granulocytes was imaged with a gamma camera and calculated by an interfaced computer before surgery and at 2, 4 and 6 h after the end of surgery. The volunteers served as a control group. In the hours after surgery the radioactivity of the area around the surgical field increased to 410.7% of initial values, while the radioactivity of the spleen decreased to 77.5%. In conclusion, the spleen constitutes a readily mobilizable source of granulocytes. This in vivo model demonstrates pronounced postoperative efflux of granulocytes to the area around the surgical field within hours.

Adult↗
PubMed2005

Prooxidant action of hinokitiol: hinokitiol-iron dependent generation of reactive oxygen species.

Hinokitiol (alpha-thujaplicin, 2-hydroxy-4-isopropyl-2,4,6-cycloheptatrien-1-one), one of the tropolone compounds purified from the woods of Chamaecyparis and Thujopsis (hinoki and hiba), produced reactive oxygen species as a complex with transition metals. Hinokitiol/iron complex inactivated aconitase, the most sensitive enzyme to reactive oxygen, whereas it did not affect aldolase and glyceraldehyde 3-phosphate dehydrogenase. The inactivation of aconitase was iron-dependent, and prevented by TEMPOL, a scavenger of reactive oxygen species and superoxide dismutase, suggesting that the hinokitiol/iron-mediated generation of superoxide anion is responsible for the inactivation of aconitase. Addition of hinokitiol effectively enhanced the ascorbate/copper-mediated formation of 8-hydroxy-2'-deoxyguanosine in DNA. Cytotoxic effect of hinokitiol can be explained by its prooxidant properties: hinokitiol/transition metal complex generates reactive oxygen species causing inactivation of aconitase and production of hydroxyl radical resulting in the formation of DNA base adduct.

8-Hydroxy-2'-Deoxyguanosine↗
PubMed1985

Evidence for dopamine release and metabolism beyond the control of nerve impulses and dopamine receptors in rat substantia nigra.

In rat substantia nigra a biphasic disappearance curve of dopamine (DA) was seen after tyrosine hydroxylase inhibition by alpha-methyl-p-tyrosine (alpha-MT): the initial phase had a fast turnover and a half life of 0.5 h and the later phase had an extremely slow turnover. In contrast to the effects in striatum, neither haloperidol nor apomorphine influenced alpha-MT-induced DA disappearance in the substantia nigra. Furthermore, inhibition of impulse flow by gamma-butyrolactone prevented DA disappearance in striatum but not in the substantia nigra. Measurements of DA and 3-methoxytyramine following treatment with inhibitors of monoamine oxidase (pargyline) and catechol-O-methyl transferase (tropolone) indicated that O-methylation is a more important metabolic pathway in the substantia nigra than in the striatum. The data are interpreted to indicate that the release and metabolism of DA in the substantia nigra are largely beyond the control of nerve impulses and DA receptors. It is suggested that such an arrangement forms an important feature of autoreceptor-mediated feedback control of DA nerve cell activity.

4-Butyrolactone↗
PubMed2006

Preferential inhibition of the magnesium-dependent strand transfer reaction of HIV-1 integrase by alpha-hydroxytropolones.

Integration is a crucial step in the life cycle of human immunodeficiency virus type 1 (HIV-1); therefore, inhibitors of HIV-1 integrase are candidates for antiretroviral therapy. Two 7-hydroxytropolone derivatives (alpha-hydroxytropolones) were found to inhibit HIV-1 integrase. A structure-activity relationship investigation with several tropolone derivatives from The National Cancer Institute compound repository demonstrated that the 7-hydroxy group is essential for integrase inhibition. alpha-Hydroxytropolones preferentially inhibit strand transfer and are inhibitory both in the presence of magnesium or manganese. Lack of inhibition of disintegration in the presence of magnesium coupled with results from different cross-linking assays suggests alpha-hydroxytropolones as interfacial inhibitors. We propose that alpha-hydroxytropolones chelate the divalent metal (Mg2+ or Mn2+) in the enzyme active site. The most active compound against HIV-1 integrase in biochemical assays [2,4,6-cycloheptatrien-1-one, 2,7-dihydroxy-4-isopropyl (NSC 18806) IC50 = 4.8 +/- 2.5 microM] exhibits weak cytoprotective activity against HIV-1(IIIB) in a cell-based assay. alpha-Hydroxytropolones represent a new family of inhibitors for the development of novel drugs against HIV infection.

Catalytic Domain↗
PubMed2005

Inhibition of human immunodeficiency virus type 1 reverse transcriptase, RNase H, and integrase activities by hydroxytropolones.

Human immunodeficiency virus type I reverse transcriptase (RT) possesses distinct DNA polymerase and RNase H sites, whereas integrase (IN) uses the same active site to perform 3'-end processing and strand transfer of the proviral DNA. These four enzymatic activities are essential for viral replication and require metal ions. Two Mg2+ ions are present in the RT polymerase site, and one or two Mg2+ ions are required for the catalytic activities of RNase H and IN. We tested the possibility of inhibition of the RT polymerase and RNase H as well as the IN 3'-end processing and transfer activities of purified enzymes by a series of 3,7-dihydroxytropolones designed to target two Mg2+ ions separated by approximately 3.7 angstroms. The RT polymerase and IN 3' processing and strand transfer activities were inhibited at submicromolar concentrations, while the RNase H activity was inhibited in the low micromolar range. In all cases, the lack of inhibition by tropolones and O-methylated 3,7-dihydroxytropolones was consistent with the active molecules binding the metal ions in the active site. In addition, inhibition of the DNA polymerase activity was shown to depend on the Mg2+ concentration. Furthermore, selective inhibitors were identified for several of the activities tested, leaving some potential for design of improved inhibitors. However, all tested compounds exhibited cellular toxicity that presently limits their applications.

Enzyme Inhibitors↗
PubMed1986

Indium-111 leucocyte scintigraphy in the investigation and management of inflammatory bowel disease.

The results of indium-111 tropolonate leucocyte scintigraphy in 105 patients with known inflammatory bowel disease are reviewed. Scintigraphy is as sensitive as radiology in detecting and assessing the extent of active colonic disease, and probably more sensitive in assessing small bowel disease. In a further 40 patients scintigraphy was successfully used as a screening test to identify, or exclude, bowel inflammation in patients with gastrointestinal symptoms. Scintigraphy has advantages over barium studies, being safe, non-invasive, more sensitive than small bowel radiology and giving additional information such as the bowel identification of intra-abdominal abscesses. The time required to label the leucocytes (about 2 hours) and the higher unit cost, unless many scintigrams are performed, are disadvantages.

Adult↗
PubMed1985

In-111 labeled leukocytes: a review of problems in image interpretation.

Leukocyte suspensions labeled with In-111 oxine or tropolone were administered intravenously to 150 patients for the detection of suspected foci of bacterial infection by gamma camera imaging. The results were correlated with other imaging modalities, and clinical, laboratory, and surgical findings after a minimum follow-up period of six months. Twenty-five of 29 foci of bacterial infection were demonstrated on the leukocyte-labeled images (sensitivity of detection = 86%). Three of the four missed lesions were chronic active osteomyelitis. The specificity of detection proved difficult to define, varying with different criteria for a false positive diagnosis. In every region of the body, a variety of lesions other than foci of bacterial infection produced positive uptake of the labeled leukocytes. An intense focal uptake was uncommon in lesions other than abscesses and hematomas. It was concluded that imaging with labeled leukocytes is valuable for demonstrating sites of infection in conjunction with other diagnostic methods. Detectable leukocytic infiltration, however, may occur in inflammatory lesions of any cause and in some noninflammatory states as well.

Abdomen↗