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PubMed1983

Binding of an indole derivative to micelles as quantified by phase-sensitive detection of fluorescence.

Phase-sensitive detection of fluorescence was used to measure the fractional binding of an amphipathic derivative of indole to detergent micelles. By selection of the detector phase angle, the emissions from the free and bound indole could be individually suppressed. The phase-sensitive intensity was then proportional to the concentrations of the bound and free indole, respectively. Also, the ratio of the phase-sensitive intensities, recorded at the phase angles for suppression, revealed the ratio of the fluorophore present in each environment. As the detergent concentration was increased, the measurements revealed a cooperative formation of detergent micelles and binding of the indole derivative to these micelles. The theory and procedures for this specific analysis can be applied to the analysis of any association reaction in which one of the species is fluorescent, and in which the fluorescence lifetime is altered by the binding process. An advantage of this procedure is that binding can be quantified without physical separation of the individual species.

Colloids↗

PubMed1978

Decomposition in foods (chemical methods). Fluorometric determination of indole in shrimp.

A fluorometric method is described for determining indole in shrimp. The indole is extracted with n-hexane, partitioned into a methanol-saturated sodium chloride solution (9+1), and determined fluorometrically. The detection limit of the method is 0.04 microgram indole/g shrimp. Quantitative analytical data are presented for indole in samples of shrimp determined by the fluorometric method and the AOAC official colorimetric and gas-liquid chromatographic procedures. The correlation coefficient between the data of the fluorometric and colorimetric methods was 0.96. Indole recovered from 25 g samples of fresh shrimp spiked with 6 and 12 microgram indole/25 g ranged from 97 to 106%. The fluorescence response is linear in the range of 1 to 25 microgram indole/100 ml methanol solution and no significant change is noted in solutions kept in the dark 18 hr.

Decapoda↗

PubMed1981

Ultraviolet detection procedure for liquid chromatographic determination of indole in shrimp.

In an ultraviolet detection procedure, indole was extracted from shrimp by blending with carbonate buffer and then partitioned into ethyl acetate. Before quantitation by high pressure liquid chromatography (HPLC), interferences were removed by the use of a polyamide cleanup column. Concentrated column effluent was injected into the chromatograph. Indole was detected by monitoring absorbance at 217 nm and quantitated by comparison of indole peak height to that of an internal standard, 2-methylindole. Recoveries of indole ranged from 72 to 117%. Results agreed well with those by the official AOAC gas-liquid chromatographic (GLC) method.

Animals↗

PubMed1994

Effect of newly synthesized indole derivatives on multidrug resistance in human cancer cells.

Twenty indole derivatives were investigated for their ability to reverse multidrug resistance (MDR), for their ability to compete with [3H]azidopine in binding to P-glycoprotein (P-gp) and for their hydrophobicity. Six derivatives almost completely reversed the resistance to vincristine (VCR) in multidrug-resistant KB-C2 cells, and other derivatives partially overcame the resistance. The ability of the derivatives to enhance vincristine cytotoxicity did not significantly correlate with the inhibition of [3H]azidopine binding to P-gp or with their hydrophobicity. However, all the derivatives that inhibited > 50% of the photolabeling completely reversed VCR resistance. The 2-pyridyl group with a basic nitrogen atom attached at position 3 of indole in an appropriate spatial orientation seems to be an important feature for the interaction of the indole derivatives with P-gp. One of the derivatives, 1, which has low cytotoxicity and hydrophobicity, completely reversed the resistance of KB-C2 cells to Adriamycin, actinomycin D and VCR. Our data indicate that MDR-reversing indole derivatives with low cytotoxicity and hydrophobicity exist. These characteristics will surely be profitable for clinical use.

ATP Binding Cassette Transporter, Subfamily B, Mem↗

PubMed1993

Molecular mechanism of delta-selectivity of indole analogs of nonpeptide opioids.

A combined experimental and computational approach was used to understand the mechanism of delta-receptor selectivity of a series of nonpeptide opioids. Six pairs of fused ring opioids/indole derivatives were studied. Receptor-binding assays using [3H][D-Ala2-MePhe4-Gly-ol]-enkephalin (mu), [3H][D-Pen2-D-Pen5]-enkephalin (delta), and [3H]U-69593 (kappa) were performed in guinea pig whole-brain membranes. Agonist activity was determined in norbinaltorphimine- or beta-funaltrexamine-treated guinea pig ileum (mu and kappa) and beta-funaltrexamine-treated mouse vas deferens (delta). Steric and electronic properties were calculated for each compound. Although the parent compounds were selective for the mu-receptor, the indole analogs displayed selectivity for the delta-site because of a decrease in mu-affinity accompanied by an increase in delta-affinity. The indole analogs displayed little or no activity at the delta-receptor. The role of the indole in enhanced delta-recognition is likely interaction with a lipophilic site in the receptor. The diminished mu-affinity of the indole analogs is a result of the loss of the carbonyl oxygen as the proton-accepting center, which we have previously determined to be important for recognition of the mu-receptor.

Amino Acid Sequence↗

PubMed1993

New pyridazino[4,5-b]indole derivatives with inodilator and antiaggregatory activities.

Some 4-(3,5-dimethylpyrazol) 5H-pyridazino [4,5-b]indoles (7), 1,2,4-triazolo [4,3-b]pyridazino [4,5-b]indoles (9) and 1,2,4-tetrazolo [4,5-b]pyridazino [4,5-b] indoles (11) substituted in position 1 by amino groups have been synthesized and tested as inotropic agents and inhibitors of platelet aggregation. 6-Imidazolyl-11H-1,2,4-triazolo [4,3-b]pyridazino [4,5-b]indole (9) shows an activity superior to that of amrinone, with a notable selectivity towards phosphodiesterase (PDE) IV and PDEV, vasodilator activity and a good effect on blood platelet aggregation.

Animals↗

PubMed1995

Mechanisms of tumor modulation by indole-3-carbinol. Disposition and excretion in male Fischer 344 rats.

This study describes the disposition and excretion of indole-3-carbinol (I3C), a natural dietary tumor modulator and candidate chemopreventive agent, in male Fisher 344 rats after continuous dietary or a single oral administration. Steady-state urinary and fecal excretion were attained 40 and 112 hr, respectively, after commencing continuous exposure. These two routes accounted for approximately 75% of the administered dose, of which 77% appeared in feces. After 7 days of 2,000 ppm dietary I3C, a mean of 1,154 microM I3C eq was found in liver, of which 17% was present as extractable, unbound I3C derivatives. Total equivalents in liver decreased to 643 and 411 microM 24 and 48 hr later, respectively, for animals returned to control diet. Mean levels of I3C eq in lung decreased from 436 to 219 microM, and blood levels decreased from 320 to 208 microM over the same 48-hr period. After administration of 1 mmol/kg radioinert I3C (a comparable daily dose as in the feeding study) for 6 days, animals were given 1 mmol/kg [3H]I3C. Mean liver levels were 257, 283, and 541 microM I3C eq at 1.5, 3, and 6 hr after dosing, and these levels represented 0.97%, 1.34%, and 2.45% of the total I3C dose administered, respectively. Concentrations of I3C eq changed little in blood, kidney, tongue, or lung over this time period. HPLC analysis of ethyl acetate extracts of liver from rats given an oral dose revealed 24 distinct [3H]I3C-derived peaks. Two of the predominant peaks were identified as 3,3'-diindolylmethane (I33', a linear dimer of I3C) and [2-(indol-3-ylmethyl)-indol-3-yl]indol-3-ylmethane (LT, a linear trimer). A novel I3C metabolite was identified as 1-(3-hydroxymethyl)-indolyl-3-indolylmethane (HI-IM). Hepatic levels of these metabolites and three major, but unidentified, products were between 1.0 and 13.1 microM; highest levels were observed at 6 hr or, for HI-IM, at 1.5 hr postdosing. Parent I3C was not detected in liver extracts, whereas the potent Ah receptor agonist 3,2-b-indolocarbazole (ICZ) was estimated at 1.6 nM. These data suggest that neither I33', LT, or ICZ alone reach sufficient hepatic concentration to account for cytochrome P450IA induction by dietary I3C, or provide effective inhibition of microsomal bioactivation of the hepatocarcinogen aflatoxin B1; however, the total hepatic mixture of I3C derivatives may be sufficient to provide both modulatory responses in the rat.

Administration, Oral↗

PubMed1977

[Research on nitrogen heterocyclic compounds. XI. - New synthesis of 3H-benz(e)indole and its derivatives].

Glutaconic esters bearing a 2-naphthylamino moiety and a carbethoxy group at the 4-position underwent thermal decomposition to give 1-carbethoxy-3H-benz[e]indole derivatives. Alkaline hydrolysis of 1-carbethoxy-3H-benz[e]indoles gave the corresponding 3H-benz[e]indoles by loss of the carboxylic group. By this method were synthesized the known 3H-benz[e5indole and the 7-methoxy-3H-benz[e]indole. Glutaconic esters used in this procedure were prepared by condensation of ethyl propiolate with the appropriate 2-naphthylaminomalonate ethyl ester in the presence of a catalytic amount of sodium ethylate.

Catalysis↗

PubMed1976

Effect of pair-feeding of carcinogen on the incidence of bladder tumors in hamsters. Role of indole, age, and sex.

The role of indole in 2-acetylaminofluorene (AAF) bladder tumorigenesis was critically evaluated in hamsters. To avoid the influence of a nutritional factor on the tumor incidence, the animals were pair-fed for 8, 10, and 12 months. Addition of indole to the AAF diet resulted in a higher incidence of bladder tumors in both males and females (P less than 0.05, P less than 0.05). Indole definitely increased the bladder tumor incidence at 8 months (P less than 0.05). Also significantly different was the tumor incidence between males and females irrespective of the diet administered (P less than 0.05). Indole did not alter the urinary output of N-hydroxy-2-acetylaminofluorene (N-OH-AAF) in males.

2-Acetylaminofluorene↗

PubMedDate not supplied

3-(Octadecanoylaminomethyl)indole-2-carboxylic acid derivatives and 1-methyl-3-octadecanoylindole-2-carboxylic acid as inhibitors of cytosolic phospholipase A2.

3-(1-Acylaminooctadecyl)indole-2-carboxylic acids and 3-(1-acylaminooctadecyl)-1-methylindole-2-carboxylic acids were designed and synthesized as inhibitors of cytosolic phospholipase A2. Enzyme inhibition was assayed by evaluation of calcium ionophore A23187-induced arachidonic acid release from bovine platelets. While compounds with 1-octadecanoylaminooctadecyl groups in position 3 of the indole were inactive inhibition data for 3-[1-(3-phenylpropionylamino)octadecyl]indole-2-carboxylic acids could not be evaluated because of lysis of the platelets. However 3-(octadecanoylaminomethyl)indole-2-carboxylic acid derivatives and 1-methyl-3-octadecanoylindole-2-carboxylic acid proved to be inhibitors of cytosolic phospholipase A2. The most active inhibitor was the latter compound with an IC50 of 8 microM.

Animals↗

PubMedDate not supplied

Influence of indole acetic acid on antioxidant levels and enzyme activities of glucose metabolism in rat liver.

Indole acetic acid (IAA) is an auxin and can be synthesized in animals. This compound is metabolized in vitro by peroxidase, producing reactive oxygen species. The toxic effect of indole acetic acid in leukocytes is associated with peroxidase activities and these processes have been implicated in activation of glucose and glutamine metabolism. However, studies in vitro have shown that IAA, in absence of peroxidase, is an antioxidant almost as high in potency as those of other indolic compounds. The purpose of this study was to investigate the possible involvement of a toxic effect of indole acetic acid in the liver, as evidenced by oxidative stress and enzyme activities of the glucose pathway. The animals received IAA by subcutaneous or gavage administration in a phosphate buffered saline (the control group received only the phosphate buffered saline). The other groups received IAA at concentrations of 1 mg, 18 mg and 40 mg per kg of body mass per day. Treatments with 18 mg and 40 mg IAA decreased the activity of catalase by both subcutaneous (30% and 26%) or gavage administration (19% and 28%), respectively. A similar effect was observed on the activity of glutathione peroxidase of animals exposed to 18 mg and 40 mg IAA: A decrease of 34% and 29%, respectively, for subcutaneous administration and a decrease of 29% and 25%, respectively, for gavage administration. However, in neither source of administration did the acid alter superoxide dismutase, glutathione reductase and myeloperoxidase activities. Another alteration was observed in respect of reduced glutathione content in this organ. The lipid peroxidation level showed a significant decrease with subcutaneous (30%, 29% and 24%) and gavage administration (25%, 26% and 24%) using 1 mg, 18 mg and 40 mg of IAA, respectively compared with the control. The reduced glutathione content and catalase activity in the plasma were not altered by either of the two methods of administration. In addition to these findings, after subcutaneous or gavage administration of IAA, the activities of hepatic enzymes of glucose metabolism were not affected (glucokinase, lactate dehydrogenase, glucose-6-phosphate dehydrogenase and citrate synthase). Evidence is presented herein that IAA did not have a pro-oxidant effect in the liver as deduced from a reduction of catalase and glutathione peroxidase activities, a decrease of lipid peroxidation content and no alteration of the pool of reduced glutathione. The effects of IAA were independent of the way of administration.

Administration, Oral↗

PubMed2007

Intra- and intermolecular reactions of indoles with alkynes catalyzed by gold.

Indoles react intramolecularly with alkynes in the presence of gold catalysts to give from six- to eight-membered-ring annulated compounds. The cationic Au(I) complex [Au(P{C(6)H(4)(o-Ph)}(tBu)(2))(NCMe)]SbF(6) is the best catalyst for the formation of six- and seven-membered rings by 6-endo-dig, 6-exo-dig, and 7-exo-dig cyclizations. Indoloazocines are selectively obtained with AuCl(3) as catalyst in a rare 8-endo-dig process. In this process allenes or tetracyclic annulated derivatives are also formed as a result of an initial fragmentation reaction. The intermolecular reaction of indoles with alkynes proceeds to form 3-alkenylated intermediates that react with a second equivalent of indole to give bisindolyl derivatives. Indoles that are substituted at the 3-position react intermolecularly with alkynes to give 2-alkenylated intermediates that can be trapped intramolecularly with the appropriate nucleophiles.

Journal Article↗

PubMed1996

3H-Indoles in Cetyltrimethylammonium Bromide (CTAB) Micelles and Water: Spectroscopy and Photophysics at Various Temperatures.

An absorption and fluorescence spectral study has been carried out for four molecules: 2-[(p-amino)phenyl]-3,3-dimethyl-3H-indole (1), 2-[(p-dimethylamino)phenyl]-3,3-dimethyl-3H-indole (2), 2-[(p-amino)phenyl]-3,3-dimethyl-5-carboethoxy-3H-indole (3), and 2-[(p-dimethylamino)phenyl]-3,3-dimethyl-5-carboethoxy-3H-indole (4) in cetyltrimethylammonium bromide (CTAB) and water solutions. Arrhenius plots for the nonradiative decay processes competing with fluorescence are nonlinear in CTAB. This is ascribed to the fact that the probes are locked into a site where the twisting of the phenyl moiety is nearly inhibited in CTAB at room temperature. The binding constants increase in an increasing order of the molecular size (exponential growth) thereby showing that hydrophobic effects are the driving force behind the solubilization of these molecules in CTAB. Calculation of transfer free energies has confirmed the importance of the hydrophobic effect compared to the Coulombic interactions. The neutral-monocation equilibrium is lowered in presence of CTAB.

Journal Article↗

PubMed1998

Influence of Polarity and Viscosity of the Micellar Interface on the Fluorescence Quenching of Pyrenic Compounds by Indole Derivatives in AOT Reverse Micelles Solutions.

The fluorescence quenching of the pyrene derivatives (4-(1-pyrenyl)butyl) trimethylammonium bromide (PBTMA), (1-(1-pyrenyl)methyl) trimethylammonium iodide (PMTMA), and 1-pyrene sulfonic acid (PSA) by indole methyl substituted in positions 1 and 2, tryptophan and tryptamine, was studied in AOT/heptane reverse micelles as a function of R = [water]/[AOT]. In these systems the pyrenic probes are associated to the micellar interface. Bulk and intramicellar quenching rate constants were determined for neutral indoles. The quenching rate constants of PBTMA by indole or 1,2-dimethylindole increase with R, whereas for those for PMTMA or PSA by indole the increment is much smaller. For the quenchers, tryptophan and tryptamine, that are bound to the interface of the reverse micelle, the bimolecular intramicellar quenching rate constant is much lower than in water. The results can be explained by a high microviscosity of the interface, and a micropolarity similar to that sensed by other probes. Moreover, the observed trend in the rate constants when R is varied is in line with the reported changes in micropolarity and microviscosity. Laser flash photolysis experiments show that in these systems the main result of the quenching process is the formation of the excited triplet of the probe. Copyright 1998 Academic Press.

Journal Article↗

PubMed2004

Erythropoiesis in patients with aggressive and indolent non-Hodgkin's lymphomas.

Parameters of the erythroid, granulocytic, and megakaryocytic hemopoietic stems were compared in 87 patients with aggressive and indolent non-Hodgkin's lymphomas before and 6 months after the start cytostatic therapy. Before chemotherapy anemia was detected in 46% patients with aggressive and 49% patients with indolent lymphomas. Hemoglobin content, peripheral blood erythrocyte count, and total count of erythroid cells in the bone marrow increased during chemotherapy in the indolent lymphoma group. Increased count of erythroid cells in the myelogram was due to decreased count of lymphoid cells in the bone marrow, which was associated with complete or partial remission. In aggressive lymphoma chemotherapy decreased the mean level of hemoglobin and mean erythrocyte count in the peripheral blood, but the total count of erythroid cells in the bone marrow increased; no relationship was detected between lymphocyte count in the bone marrow and erythropoiesis characteristics. Lymphocytosis >50% in the myelogram before chemotherapy was less frequent in this group in comparison with indolent non-Hodgkin's lymphomas.

Anemia↗

PubMed1992

Indole-N-methylated beta-carbolinium ions as potential brain-bioactivated neurotoxins.

N-Methyl-4-phenylpyridinium ion (MPP+), a highly toxic metabolite produced in the brain from a street drug contaminant, is selectively taken up by nigrostriatal dopaminergic neurons and accumulated intraneuronally in mitochondria. There it inhibits respiration, causes neuronal death and, in primates, provokes a parkinsonian condition. It has been suggested that endogenously generated or activated agents resembling MPP+ may contribute to the development of Parkinson's disease. We report here that simple beta-carbolines derived from tryptophan or related open chain indoles, when specifically methyl-substituted on both (2[beta] and 9[indole]) available nitrogens, display mitochondrial inhibitory potencies and neurotoxic effects in vitro (PC12 cultures) and in vivo (striatal microdialysis) which approach or even surpass MPP+. These results take on physiological significance with our finding that brain enzyme activity catalyzes S-adenosylmethionine-dependent methylations of the beta- and indole-nitrogens in beta-carbolines that have been detected in vivo. The unusual 9[indole]-N-methyl transfer, previously unrecognized in animals, apparently requires prior methylation of the 2[beta]-nitrogen. Sequential di-N-methylation of endogenous or xenobiotic beta-carbolines to form unique, neurotoxic 2,9-N,N'-dimethyl-beta-carbolinium ions may serve as a brain bioactivation route in chronic neurodegenerative conditions such as Parkinson's disease.

Adenosine Diphosphate↗

PubMed1996

Parasympathetic inhibition of pineal indole metabolism by prejunctional modulation of noradrenaline release.

The role of the parasympathetic nervous system in rat pineal indole metabolism was investigated by transpineal in vivo microdialysis. On-line coupling to a high performance liquid chromatography system with fluorescence detection (HPLC-FD) allowed simultaneous analysis of three major indolic compounds from the pineal, i.e. serotonin, N-acetylserotonin and melatonin. Infusion of the muscarinic receptor agonists, carbachol and oxotremorine, during the dark period resulted in a marked decrease of melatonin release. This effect was suggested to be mediated by a decrease in N-acetyltransferase activity, since a similar decrease was seen in N-acetylserotonin release, while serotonin levels increased simultaneously. Nicotine did show a very slight effect on the three indoles under these circumstances. Neostigmine failed to influence pineal indole metabolism, indicating that the endogenous tonus of acetylcholine release is either absent or extremely low in the middle of the dark period. The involvement of sympathetic innervation in the muscarinic effects was investigated by measurement of noradrenaline release from the pineal by sensitive off-line HPLC-FD analysis of noradrenaline in the dialysates. Carbachol markedly decreased the noradrenaline input during the infusion. Noradrenaline release returned to baseline values immediately after infusion with carbachol. These data suggest that the in vivo inhibitory effect of muscarinic receptor agonists on pineal melatonin production is mediated by presynaptic muscarinic receptors, located on the sympathetic nerve endings. This prejunctional inhibition of noradrenaline release causes a reduced induction of N-acetyltransferase activity, resulting in decreased melatonin release.

Animals↗

PubMed1988

Mechanisms of serum protein binding and cell anchorage to immobilized serotonin and indole analogs.

Bovine aortal endothelial cells, bovine smooth muscle cells, chick embryo fibroblasts, and baby hamster kidney cells all attached and grew on immobilized tryptamine or L-tryptophan as successfully as on immobilized serotonin. A detailed investigation employing different serum compositions combined with cell blotting and immunoblotting techniques revealed that adhesion of cells to each of the immobilized indole analogs was mediated by vitronectin and fibronectin. Quantitative analyses revealed major differences in the variety of serum proteins adsorbed to each of the immobilized indole analogs and in particular major differences in the amounts of adsorbed vitronectin. However, similar levels of adsorbed fibronectin and fibronectin fragments were found on each of the immobilized indole analogs. The results indicate that (i) different composites of surface-adsorbed proteins may be directed by chemical differences between the immobilized indole analogs and (ii) mammalian cells may still populate chemically different surfaces with equal success despite differences in the surface profiles of adsorbed serum proteins.

Animals↗