chiniofon and carbostyril

It is known that 2-quinolones are broadly applicable chemical structures in medicinal and agrochemical research as well as various functional materials. A number of current publications about their synthesis and their applications emphasize the importance of these small molecules. The early synthetic chemistry originated from the same principle of the classical Friedländer and Knorr procedures for the preparation of quinolines. The analogous processes were developed by applying new synthetic tools such as novel catalysts, the microwave irradiation method, etc., whereas recent innovations in new bond forming reactions have allowed for novel strategies to construct the core structures of 2-quinolones beyond the bond disconnections based on two classical reactions. Over the last few decades, some reviews on structure-based, catalyst-based, and bioactivity-based studies have been released. In this focused review, we extensively surveyed recent examples of one-pot reactions, particularly in view of modular approaches. Thus, the contents are categorized as three major sections (two-, three-, and four-component reactions) according to the number of reagents that ultimately compose atoms of the core structures of 2-quinolones. The collected synthetic methods are discussed from the perspectives of strategy, efficiency, selectivity, and reaction mechanism.

Topics: Catalysis; Chemistry Techniques, Synthetic; Hydroxyquinolines; Metals; Molecular Structure; Quinolones

Carbostyril (2-quinolinone, 2-quinolone) is an important structural component frequently used in natural products and in physiologically active substances including drugs. It is a 2-ring condensed heterocyclic compound containing several positions that can be replaced by arbitrary substituent groups and is used as a chemical building block, scaffold, fragment, and pharmacophore in drug design or discovery. Since the number of compounds that can be designed using carbostyril is exceedingly large, the steric structures of carbostyril derivatives can be adjusted to the unique, spatially oriented shape of, for example, the active sites of pharmaceutical target molecules. Moreover, the internal amide of the carbostyril unit exhibits distinctive features because of the fixed cis form of the lactam amide group. Because carbostyril has been used as a component in drugs and other bioactive compounds over time, carbostyril derivatives may improve absorption, distribution, metabolism, excretion, and toxicity (ADMET). Therefore, carbostyril derivatives have enormous potential. In this review, the potential and advantages of the use of carbostyril and its related molecular skeletons, such as 3,4-dihydrocarbostyril, are discussed by focusing on the physiologically active substances in which they are incorporated.

Topics: Drug Design; Hydroxyquinolines; Molecular Structure; Quinolones

Coumarins, also referred as benzopyran-2-ones, and their corresponding nitrogen counterpart, 1-azacoumarins also referred to as carbostyrils, are a family of nature-occurring lactones and lactams respectively. The plant extracts containing coumarin-related heterocycles, which were employed as herbal remedies in early days, have now been extensively studied for their biological activities. These investigations have revealed their potentials as versatile biodynamic agents. For example, coumarins with phenolic hydroxyl groups have the ability to scavenge reactive oxygen species and thus prevent the formation of 5-HETE and HHT in the arachidonic pathway of inflammation suppression. Recent in vivo studies have revealed the role of coumarins in hepatotoxicity and also in depletion of cytochrome P450. Similarly 1-azacoumarins which is part of quinoline alkaloids, are known for their diverse biological activity and recently, a 6-functionalized 1-aza coumarins are undergoing human clinical trials as an orally active anti-tumor drug in view of its farnesyl protein-inhibiting activity in the nanomolar range. Furthermore, several synthetic coumarins with a variety of pharmacophoric groups at C-3, C-4 and C-7 positions have been intensively screened for anti-microbial, anti-HIV, anti-cancer, lipid-lowering, anti-oxidant, and anti-coagulation activities. Specifically, coumarin-3-sulfonamides and carboxamides were reported to exhibit selective cytotoxicity against mammalian cancer cell lines. The C4-substituted aryloxymethyl, arylaminomethyl, and dichloroacetamidomethyl coumarins, along with the corresponding 1-azacoumarins, have been demonstrated to be potential anti-microbial and anti-inflammatory agents. To expand the structural diversity of synthetic courmarins for biological functions, attempts have also been made to attach a chloramphenicol side chain at C-3 position of courmarin. In addition, the bi- and tri-heterocyclic coumarins and 1-azacoumarins with benzofuran, furan and thiazole ring systems along with biocompatible fragments like vanillin have shown remarkable potency as anti-inflammatory agents in animal models. Photobiological studies on pyridine-fused polycyclic coumarins have highlighted their potential as thymine dimer photosensitisers and the structurally related compounds of both coumarin and carbostyrils have also been found to act via the DNA gyrase pathway in their anti-bacterial activity. Apart from the above works, the present review also addre

Topics: Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Antineoplastic Agents; Coumarins; Humans; Hydroxyquinolines; Molecular Structure; Protease Inhibitors; Quinolones; Stereoisomerism

Due to the ever-increasing antimicrobial resistance there is an urgent need to continuously design and develop novel antimicrobial agents. Inspired by the broad antibacterial activities of various heterocyclic compounds such as 2-quinolone derivatives, we designed and synthesized new methyl-(2-oxo-1,2-dihydroquinolin-4-yl)-L-alaninate-1,2,3-triazole derivatives via 1,3-dipolar cycloaddition reaction of 1-propargyl-2-quinolone-L-alaninate with appropriate azide groups. The synthesized compounds were obtained in good yield ranging from 75 to 80 %. The chemical structures of these novel hybrid molecules were determined by spectroscopic methods and the antimicrobial activity of the compounds was investigated against both bacterial and fungal strains. The tested compounds showed significant antimicrobial activity and weak to moderate antifungal activity. Despite the evident similarity of the quinolone moiety of our compounds with fluoroquinolones, our compounds do not function by inhibiting DNA gyrase. Computational characterization of the compounds shows that they have attractive physicochemical and pharmacokinetic properties and could serve as templates for developing potential antimicrobial agents for clinical use.

Topics: Anti-Bacterial Agents; Anti-Infective Agents; Antifungal Agents; Hydroxyquinolines; Microbial Sensitivity Tests; Molecular Structure; Quinolones; Structure-Activity Relationship; Triazoles

Carbostyrils are quinolone derivatives, with possible growth inhibition properties on cancer cells. Unlike many tumors, 15-Lipoxygenase-1 (15-LOX-1) is highly expressed in prostate cancer (PCa) cells and has oncogenic properties. Here, with the hypothesis that 6-, 7- and 8-geranyloxycarbostyril (GQ) have inhibitory properties on 15-LOX-1, their effects were assessed on PCa cells. Their cytotoxic effects were evaluated by MTT assay and mechanism of cell death was investigated using annexin V/PI staining. Finally, the anti-tumor properties of 8-GQ were assessed in immunocompromised C57BL/6 mice bearing human PCa cells. Accordingly, these compounds could effectively inhibit 15-LOX activity in PCa cells. MTT and flow cytometry tests confirmed their toxic effects on PCa cells, with no significant toxicity on normal cells, and apoptosis was the main mechanism of cell death. In vivo results indicated that use of 8-GQ at 50 mg/kg had stronger anti-tumor effects than 5 mg/kg cisplatin, with fewer side effects on normal tissues. Therefore, 8-GQ can be introduced as a potential drug candidate with 15-LOX-1 inhibitory potency, which can be effective in treatment of prostate cancer, and should be considered for further drug screening investigations.

Topics: Animals; Antineoplastic Agents; Arachidonate 15-Lipoxygenase; Dose-Response Relationship, Drug; HeLa Cells; Humans; Hydroxyquinolines; Lipoxygenase Inhibitors; Male; Mice; Mice, Inbred C57BL; Prostatic Neoplasms; Quinolones; Xenograft Model Antitumor Assays

Catalyzed peroxidation of unsaturated lipid in animals and plants intimately is linked to the activity of 15-Lipoxygenase enzymes. Lipoxygenases (LOXs) are well known to play an important role in many acute and chronic syndromes such as inflammation, asthma, cancer, and allergy. In this study, a series of mono prenyloxycarbostyrils were synthesized and evaluated as potential inhibitors of soybean 15-Lipoxygenase (SLO) and their inhibitory potencies were compared to mono prenyloxycoumarins which had been reported in the previous works. The synthetic compounds inhibit lipoxygenase enzyme by competitive mechanism like the prenyloxy coumarins. The results showed that position and length of the prenyl moiety play the important role in lipoxygenase inhibitory activity. Among all of the synthetic compounds (coumarin and carbostyril derivatives), 5-farnesyloxycoumarin and 8-farnesyloxycarbostyril demonstrated the best inhibitory activity by IC

Topics: Arachidonate 15-Lipoxygenase; Biphenyl Compounds; Coumarins; Glycine max; Humans; Hydroxyquinolines; Lipoxygenase Inhibitors; Picrates; Quinolones; Structure-Activity Relationship

Topics: Acetates; Amides; Binding Sites; Coumarins; Hydroxyquinolines; Lanthanoid Series Elements; Ligands; Luminescence; Magnetic Resonance Spectroscopy; Metals; Models, Molecular; Molecular Structure; Quinolones; Spectrophotometry, Ultraviolet; Temperature

Sepsis-associated encephalopathy (SAE) is a transient and reversible brain dysfunction, that occurs when the source of sepsis is located outside of the central nervous system; SAE affects nearly 30% of septic patients at admission and is a risk factor for mortality. In our study, we sought to determine whether metabolite changes in plasma could be a potential biomarker for the early diagnosis and/or the prediction of the prognosis of sepsis.. A total of 31 SAE patients and 28 healthy controls matched by age, gender, and body mass index (BMI) participated in our study. SAE patients were divided into four groups according to the Glasgow Coma Score (GCS). Plasma samples were collected and used to detect metabolism changes by gas chromatography-mass spectrometry (GC-MS). Analysis of variance was used to determine which metabolites significantly differed between the control and SAE groups.. We identified a total of 63 metabolites that showed significant differences among the SAE and control groups. In particular, the 4 common metabolites in the four groups were 4-hydroxyphenylacetic acid; carbostyril, 3-ethyl-4,7-dimethoxy (35.8%); malic acid peak 1; and oxalic acid. The concentration of 4-hydroxyphenylacetic acid in sepsis patients decreased with a decrease of the GCS.. According to recent research on SAE, metabolic disturbances in tissue and cells may be the main pathophysiology of this condition. In our study, we found a correlation between the concentration of 4-hydroxyphenylacetic acid and the severity of consciousness disorders. We suggest that 4-hydroxyphenylacetic acid may be a potential biomarker for SAE and useful in predicting patient prognosis.

Topics: Aged; Biomarkers; Body Mass Index; Early Diagnosis; Female; Gas Chromatography-Mass Spectrometry; Glasgow Coma Scale; Humans; Hydroxyquinolines; Intensive Care Units; Malates; Male; Metabolomics; Middle Aged; Oxalic Acid; Phenylacetates; Prognosis; Quinolones; Sepsis; Sepsis-Associated Encephalopathy

Antibiotics are widely used to improve the health and yields of farmed animals, including fish, but their use is accompanied by undesirable ecological effects. Relatively little is known about the water-body burden of antibiotics and their influence on primary productivity in aquaculture ecosystem. In this study, antibiotics usage within 24 fishponds, covering 4 areas, sampled 5 times, and having 5 fish species, was investigated surrounding Tai Lake in China. The study analyzed 15 antibiotics (including 5 sulfonamides, 2 quinolones, 3 β-lactams, 3 tetracyclines, 1 amphenicol, and 1 macrolide), and all of them were detected in water samples, with a detection frequency of 2-60%. Sulfonamides were the most prevalent, and concentrations of sulfamethoxazole, sulfamonomethoxine, and florfenicol being over 2000 ng L(-1) in some samples, while the other antibiotics levels ranged from ND (no detection) to 551.18 ng L(-1). Significant differences were observed in antibiotic burden among different regions for total antibiotics, sulfonamides, quinolones, and amphenicols; among time points for quinolones, β-lactams, and tetracyclines; and among species for quinolones and macrolides. Furthermore, basing on the risk quotient (RQ) method, the assessment revealed that florfenicol was of highest risk to algae with RQ values exceeding 0.1, while macrolide erythromycin posed the second highest risk. The partial correlation coefficient between total antibiotics and chlorophyll (a) was -0.035 that clearly indicated total antibiotics were detrimental to green algae growth, while the nutrient input and other physical - chemical factors were much more beneficial. Overall, holistic far-reaching measures of antibiotics control are recommended to preserve aquaculture ecosystem health.

Topics: Animals; Anti-Bacterial Agents; beta-Lactams; China; Environmental Monitoring; Fishes; Hydroxyquinolines; Lakes; Macrolides; Quinolones; Sulfonamides; Tetracyclines; Thiamphenicol; Water Pollutants, Chemical

Free NH 3,3-diarylacrylamides are cyclized to substituted 2-quinolones in the presence of CuI, PPh(3), and KO-t-Bu in o-xylene at 100 °C. The reaction proceeds through a C-H functionalization/C-N bond formation process. With unsymmetrical 3,3-diarylacrylamides, high selectivity is observed using substrates where the aromatic ring trans to the amide group bears o-methyl, -chloro, or -bromo substituents.

Topics: Amides; Catalysis; Copper; Cyclization; Hydroxyquinolines; Iodides; Molecular Structure; Quinolones

3-Aryl-2-quinolone derivates were extensively investigated for their inhibition of farnesyl transferase. Taking this as a cue, we studied the other possible mechanism of antitumor activity of 2-quinolone derivates. A series of new 2-quinolone derivatives have been synthesized and screened for their cytotoxicity by trypan blue assay on Ehrlich ascites carcinoma cells and MTT assay on MCF-7 cells. Compound 1a (nJST) was found to be more effective in both studies with the lowest CTC(50) value among all nine synthesized compounds. This compound was further screened on four different cell lines, viz. human breast adenocarcinoma (MCF-7, MDA-MB-231), colon cancer (HCT-15), murine melanoma (B16F10) cell lines for 24 and 48 h. The CTC(50) value of the compound was found to be <10 μm. Compound 1a induced DNA damage which was revealed by DNA fragmentation studies and further confirmed by nuclear staining. The compound also showed significant elevation in Bax and reduction Bcl-2 gene expression levels. Acute toxicity study in mice indicated that the compound is safe till 2000 mg/kg. Two different doses 50 and 100 mg/kg were selected and studied in Ehrlich ascites carcinoma model of cancer and have shown significant improvement in survival time and hematological parameters.

Topics: Animals; Antineoplastic Agents; Apoptosis; bcl-2-Associated X Protein; Breast Neoplasms; Carcinoma, Ehrlich Tumor; Cell Line, Tumor; Cell Survival; DNA Fragmentation; Female; Gene Expression Regulation, Neoplastic; Humans; Hydroxyquinolines; Mice; Neoplasms; Quinolones

Melanomas display poor response rates to adjuvant therapies because of their intrinsic resistance to proapoptotic stimuli. This study indicates that such resistance can be overcome, at least partly, through the targeting of eEF1A elongation factor with narciclasine, an Amaryllidaceae isocarbostyril controlling plant growth. Narciclasine displays IC(50) growth inhibitory values between 30-100 nM in melanoma cell lines, irrespective of their levels of resistance to proapoptotic stimuli. Normal noncancerous cell lines are much less affected. At nontoxic doses, narciclasine also significantly improves (P=0.004) the survival of mice bearing metastatic apoptosis-resistant melanoma xenografts in their brain. The eEF1A targeting with narciclasine (50 nM) leads to 1) marked actin cytoskeleton disorganization, resulting in cytokinesis impairment, and 2) protein synthesis impairment (elongation and initiation steps), whereas apoptosis is induced at higher doses only (≥200 nM). In addition to molecular docking validation and identification of potential binding sites, we biochemically confirmed that narciclasine directly binds to human recombinant and yeast-purified eEF1A in a nanomolar range, but not to actin or elongation factor 2, and that 5 nM narciclasine is sufficient to impair eEF1A-related actin bundling activity. eEF1A is thus a potential target to combat melanomas regardless of their apoptosis-sensitivity, and this finding reconciles the pleiotropic cytostatic of narciclasine. -

Topics: Amaryllidaceae Alkaloids; Animals; Antineoplastic Agents; Apoptosis; Binding Sites; Cell Line, Tumor; Cytoskeleton; Drug Delivery Systems; Gene Expression Regulation; Humans; Hydroxyquinolines; Liliaceae; Melanoma; Mice; Models, Molecular; Peptide Elongation Factor 1; Phenanthridines; Quinolones; Saccharomyces cerevisiae

We have carried out a detailed photophysical study of the FRET D/A pair consisting of a carbostyril donor and a Ru(II)bathophenanthroline complex acceptor in double-stranded synthetic DNA. Altogether 13 different double-stranded 30 base pair DNAs showing small incremental differences in the distances between donor and acceptor were synthesized. Using the fluorescence of the donor as well as of the acceptor, D/A separations were determined and compared to those derived from a well-established model for DNA distance calculations. The model calculations and anisotropy studies revealed that the donor can nearly be seen as a free rotator allowing the application of the established FRET data evaluation.

Topics: Base Sequence; DNA; Fluorescence; Fluorescence Resonance Energy Transfer; Fluorescent Dyes; Hydroxyquinolines; Models, Molecular; Oligonucleotides; Organometallic Compounds; Phenanthrolines; Photoelectron Spectroscopy; Quinolones; Spectrometry, Fluorescence

Fluorescent probes based on a 6-hydroxycarbostyril core accumulate inside neurons and astroglia in the absence of a serotonin uptake inhibitor.

Topics: Animals; Astrocytes; Chickens; Fluorescent Dyes; Hydroxyquinolines; Neurons; Quinolones; Selective Serotonin Reuptake Inhibitors; Serotonin; Serotonin Plasma Membrane Transport Proteins

The use of ozonation for the purification of drinking water can lead to the formation of bromate. The US Environmental Protection Agency and the European Directive for human drinking water has lowered the regulatory level for bromate down to 10 microg l(-1), such that methods must be developed for monitoring the formation of bromate, particularly in on-site situations. In the present work we report a fluorometric method for the determination of bromate based on the reaction with carbostyril-124, a compound that shows fluorescence mainly at pH values above 4 and, when bromated, generates a non-fluorescent product. The reaction can thus be used as an indirect method for determination of the ion. The proposed method, which uses the flow injection (FI) technique, allows online application and kinetic control of the variables affecting the process, together with shorter reaction times, and it provides maximum sensitivity and selectivity. Under optimum conditions, it is possible to determine the analyte within the 4-200 microg l(-1) range, with a limit of detection of 0.9 microg l(-1) and a relative standard deviation (n=12, [BrO3-]=5 and 30 microg l(-1)) of 3.2% and 2.6% respectively. The determination rate was ten samples per hour.

Topics: Bromates; Flow Injection Analysis; Fluorescence; Hydroxyquinolines; Ozone; Quinolones; Sensitivity and Specificity; Water; Water Purification

The quenching of terbium emission in the sensitized complex Tb3+-cs124-DTPA by nitroxide radical TEMPO derivatives in aqueous solutions has been studied with time-averaged and time-resolved methods. The time-resolved results show more quenching than the time-averaged values, opposite to the behavior expected for static quenching. A rapid exchange model with a slightly fluorescent fluorophore/quencher complex is proposed. Due to the long time scale of Tb3+ emission, dynamical averaging must be considered in the interpretation of experiments. The rapid exchange limit is shown to be consistent with the present results. The utility of these observations in the design of sensors that are not limited by a background level is noted.

Topics: Chelating Agents; Cyclic N-Oxides; Free Radicals; Hydroxyquinolines; Kinetics; Luminescent Measurements; Nitrogen Oxides; Organometallic Compounds; Pentetic Acid; Quinolones; Terbium

Hypochlorite (HOCl) attacks amino acid residues in LDL making the particle atherogenic. Tryptophan is prone to free radical reactions and modification by HOCl. We hypothesized, that free tryptophan may quench the HOCl attack therefore protecting LDL. Free tryptophan inhibits LDL apoprotein modification and lipid oxidation. Tryptophan-HOCl metabolites associate with LDL reducing its oxidizability initiated by endothelial cells, Cu(2+) and peroxyl radicals. One tryptophan-HOCl metabolite was identified as 4-methyl-carbostyril which showed antioxidative activity when present during Cu(2+) mediated lipid oxidation, but did not associate with LDL. Indole-3-acetaldehyde, a decomposition product of tryptophan chloramine (the product of the tryptophan-HOCl reaction) was found to associate with LDL increasing its resistance to oxidation. Myeloperoxidase treatment of LDL in the presence of chloride, H(2)O(2) and tryptophan protected the lipoprotein from subsequent cell-mediated oxidation. We conclude that, in vivo, the activated myeloperoxidase system can generate antioxidative metabolites from tryptophan by the reaction of hypochlorite with this essential amino acid.

Topics: Acetaldehyde; Cells, Cultured; Copper; Endothelial Cells; Humans; Hydroxyquinolines; Hypochlorous Acid; Lipid Metabolism; Lipid Peroxidation; Lipoproteins, LDL; Oxidation-Reduction; Quinolones; Tryptophan

Beginning with the structure of tipifarnib (1), a series of inhibitors of FTase have been synthesized by transposition of the D-ring to the imidazole and subsequent modification of the 2-quinolone motif. The compounds in the new series may be achiral and have structural features that allow for analogs that are difficult or impossible to make in the tertiary carbon-based tipifarnib series. The most potent compound (4d) is 4 times more active in vitro against FTase than tipifarnib.

Topics: Alkyl and Aryl Transferases; Animals; Cattle; Drug Design; Enzyme Inhibitors; Farnesyltranstransferase; Hydroxyquinolines; Indoles; Mice; NIH 3T3 Cells; Quinolones; Stereoisomerism

We have surveyed the utility of Beckmann rearrangement for the conversion of indanones into carbostyrils. Initial attempts at the conversion of 6-methoxy indanone oxime under classical conditions resulted in the formation of the two unusual products: 2-sulfonyloxyindanone and the dimeric product. This unusual rearrangement was also observed by the treatment of some metal triflates species. Further investigation has led to the development of reliable conditions starting from oxime mesylate (not oxime tosylate), in which some strong Lewis acid catalyst (ZrCl(4)) was employed in either a conventional or non-conventional solvent system. The advantage of the new protocol is highlighted by the simple work up and direct isolation of the product in 65% isolated yield.

Topics: Alkanesulfonates; Catalysis; Chlorides; Hydroxyquinolines; Indans; Isomerism; Mesylates; Metals; Organometallic Compounds; Oximes; Quinolones; Solvents; Zirconium

Attempted Beckmann rearrangement of the 6-methoxyindanone oximes in conventional conditions resulted in the formation of the two kinds of unexpected products: 2-sulfonyloxyindanone and the dimeric product. Related rearrangement was also observed in the reaction with RhCl-trifluoromethansulfonic acid system.

Topics: Catalysis; Hydroxyquinolines; Indans; Indicators and Reagents; Isomerism; Magnetic Resonance Spectroscopy; Oximes; Quinolones

Several carbostyril-based beta-agonists have been shown to bind tightly to and slowly dissociate from the beta2-adrenoceptor (beta2AR). In the present study, the structural features of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] -carbostyril (11a) which contribute to its binding properties at the beta2AR were investigated using a series of synthesized analogs. The k(off), estimated by the rate of cAMP decline in DDT1 MF-2 (DDT) cells with a reduced receptor density, Ki and ligand-induced receptor reductions were determined. All of the derivatives stimulated cAMP accumulation in DDT cells in the sub to mid nanomolar range and elicited the same maximal stimulation as (-)isoproterenol. Derivatives of 11a with side chain N-substitutions comprising 2-methylbutyl, phenylethyl and isopropyl had higher k(off)-values and lower affinities as compared to 11a. Increasing the number of methylenes between the side chain tertiary alpha carbon and phenyl from 1 in 11a to 3 or reducing the number to 0 also resulted in derivatives with higher k(off)- and Ki-values. In addition, replacement of the 8-hydroxycarbostyril nucleus of 11a with catechol reduced the affinity of the compound for the beta2AR by 48-fold and increased its k(off). Only those derivatives with the lowest k(off)-values induced a decrease in the receptor density of DDT cell membranes following a preincubation and extensive washing. The data show that the 8-hydroxycarbostyril nucleus in conjunction with substitutions on the tertiary alpha carbon of the side chain and positioning of the phenyl group are important characteristics determining the high affinity and slow dissociation of 11a from the beta2AR.

Topics: Adrenergic beta-Agonists; Catechols; Cell Culture Techniques; Cell Line; Cyclic AMP; Hydroxyquinolines; Isoproterenol; Ligands; Linear Models; Phosphoric Diester Hydrolases; Quinolones; Receptors, Adrenergic, beta-2; Structure-Activity Relationship; Time Factors

1. The chemoreactive ligands 5(2-(((1'-(4'-isothiocyanatophenylamino)thiocarbonyl)-amino) -2-methylpropyl)amino-2-hydroxypropoxy)-3,4-dihydrocarbostyril (DCITC) and 8-hydroxy-5(2-(((1'-(4'-isothiocyanatophenylamino)thiocarbonyl+ ++)amino)-2-methylprop-2-yl)amino-1-hydroxyethyl)-carbostyril++ + (HCITC) were synthesized and shown to be potent irreversible antagonist and agonist ligands, respectively, for the beta-adrenoceptor in DDT1 MF-2 (DDT) cells and the rat isolated aorta. 2. In DDT cell membranes DCITC and HCITC inhibited (-)[125I]-iodocyanopindolol (CYP) binding to the beta-adrenoceptor with IC50 values of 1.1 and 18 nM, respectively. (-)-Isoprenaline inhibited [125I]-CYP binding with an IC50 of 355 nM. Pretreatment of membranes with either chemoreactive ligand produced a time- and concentration-dependent decrease in the beta-adrenoceptor content, indicating irreversible receptor binding. DCITC at concentrations up to 10 microM did not stimulate cyclic AMP accumulation in DDT cells nor did it amplify forskolin-stimulated cyclic AMP accumulation. 3. In the rat isolated aorta, DCITC (0.1 microM) did not affect either the phenylephrine-mediated tissue contraction or the acetylcholine-mediated relaxation. DCITC attenuated the maximal (-)-isoprenaline-mediated relaxation of a phenylephrine contracted aorta in a concentration-dependent manner and shifted the dose-response curves for (-)-isoprenaline to the right. The DCITC-induced decrease in maximal response was not reversed by extensive tissue washing. By use of the operational model of agonism, the calculated dissociation constant for (-)-isoprenaline ws 286 nM and the estimated receptor reserve for this agonist was 23% at the maximal response. 4. HCITC and (-)-isoprenaline stimulated cyclic AMP accumulation in DDT cells with pD2 values (negative logarithm to base 10 of EC50) of 7.95 and 7.97, respectively, and both mediated the same maximal stimulation. In the rat isolated aorta, HCITC produced a concentration-dependent relaxation of the tissue with a pD2 value of 6.62, whereas the pD2 for (-)-isoprenaline was 7.03. However, HCITC produced a greater maximal relaxation of the tissue than (-)-isoprenaline. The HCITC-mediated stimulation of cyclic AMP accumulation and relaxation of the isolated tissue were blocked when the beta-antagonist propranolol was added concurrently. In contrast, once the HCITC-mediated responses were established, the addition of propranolol did not result in any attenuation indica

Topics: Adrenergic beta-Agonists; Adrenergic beta-Antagonists; Animals; Aorta; Cell Line; Hydroxyquinolines; In Vitro Techniques; Isoproterenol; Male; Quinolones; Rats

We extend the technique of fluorescence resonance energy transfer (FRET) by introducing a luminescent terbium chelate as a donor and an organic dye, tetramethylrhodamine, as an acceptor. The results are consistent with a Förster theory of energy transfer, provided the appropriate parameters are used. The use of lanthanide donors, in general, and this pair, in particular, has many advantages over more conventional FRET pairs, which rely solely on organic dyes. The distance at which 50% energy transfer occurs is large, 65 A; the donor lifetime is a single exponential and long (millisecond), making lifetime measurements facile and accurate. Uncertainty in the orientation factor, which creates uncertainty in measured distances, is minimized by the donor's multiple electronic transitions and long lifetime. The sensitized emission of the acceptor can be measured with little or no interfering background, yielding a > 25-fold improvements in the signal-to-background ratio over standard donor-acceptor pairs. These improvements are expected to make distances > 100 A measurable via FRET. We also report measurement of the sensitized emission lifetime, a measurement that is completely insensitive to total concentration and incomplete labeling.

Topics: Base Sequence; Chelating Agents; DNA; Energy Transfer; Fluorescent Dyes; Hydroxyquinolines; Kinetics; Molecular Sequence Data; Oligodeoxyribonucleotides; Pentetic Acid; Quinolones; Rhodamines; Spectrometry, Fluorescence; Terbium

Derivatives carrying a substituent in the para position of the phenyl group of 8-hydroxy-5-[2-[(1-phenyl-2-methylprop-2-yl)amino]-1-hydroxyethyl] carbostyril (10) were prepared and their effects on beta-adrenoceptors evaluated in vitro. Unsubstituted compound 10, iodo 11, amino 12, and bromoacetamido 13 derivatives (all racemic) bound to the receptor with 15-100-fold lower dissociation constants than that of (-)-isoproterenol. All the above compounds stimulated adenylate cyclase more potently than (-)-isoproterenol. The intrinsic activities of compounds 10 and 12 were equal to that of (-)-isoproterenol. The intrinsic activities of compounds 11 and 13 were 1.3 and 1.2 times that of (-)-isoproterenol, respectively. Treatment of membrane preparations with bromoacetamido derivative 13 resulted in an irreversible loss of binding sites, and thus, 13 seems to be an alkylating affinity label for beta-adrenoceptors.

Topics: Adenylyl Cyclases; Adrenergic beta-Agonists; Animals; Hydroxyquinolines; Isoproterenol; Kinetics; Membranes; Quinolones; Receptors, Adrenergic, beta; Reticulocytes

The behaviour of 3-acetylcarbostyril derivative 1, towards the Mannich reaction and the reactivity of the products formed in their reactions with aniline, phenylhydrazine and benzenesulphonyl chloride were studied. Furthermore, the reaction of 1 with thioglycolic acid was also investigated.

Topics: Aniline Compounds; Chemical Phenomena; Chemistry; Heterocyclic Compounds; Hydroxyquinolines; Mannich Bases; Phenylhydrazines; Quinolones

Topics: Hydroxyquinolines; Oxyquinoline; Quinolines; Quinolones

Topics: Antimalarials; Cinchona; Cinchona Alkaloids; Humans; Hydroxyquinolines; Malaria; Quinolones