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PubMed1964

SELECTIVE INHIBITION BY TRYPTOPHAN ANALOGUES OF MURINE TOXIN SYNTHESIS IN PASTEURELLA PESTIS.

Montie, Thomas C. (Albert Einstein Medical Center, Philadelphia, Pa.), and Samuel J. Ajl. Selective inhibition by tryptophan analogues of murine toxin synthesis in Pasteurella pestis. J. Bacteriol. 88:1467-1475. 1964.-Washed-cell suspensions of Pasteurella pestis, avirulent strain "Tjiwidej," exhibited a preferential inhibition of toxin synthesis relative to total protein formation, when grown in the presence of various tryptophan analogues. Growth was partially inhibited in the presence of methyl analogues. High concentrations of 5-fluorotryptophan induced slight growth-inhibitory effects. However, toxin production was more sensitive to these levels of the analogue. Growth inhibition appeared not to relate to toxin inhibition. Inhibition of toxin synthesis by analogues was reversed by l-tryptophan and indole. Shikimic acid but not anthranilic acid antagonized the action of 4-methyltryptophan on selective toxin synthesis. The formation of tryptophanless protein accounted for continued protein synthesis in tryptophan-depleted cells. Protein resolved by acrylamide gel electrophoresis from crude cell extracts exhibited two toxic protein bands. The synthesis of one toxin-protein band, the less-mobile of the two, appeared to be associated with the membrane fraction of the cell, and was selectively blocked in cells grown in the presence of tryptophan analogues. Cellular tryptophan levels may determine the quantity and quality of proteins made.

Animals↗
PubMed1987

Interferon-gamma-induced degradation of tryptophan by human cells in vitro.

Several human cells were investigated for their ability to degrade tryptophan and to synthesize neopterin upon induction by interferon-gamma (500 units/ml for 48 h). Concentrations of tryptophan, kynurenine, 3-hydroxykynurenine, anthranilic acid, 3-hydroxyanthranilic acid, 7,8-dihydroneopterin and neopterin were assessed in the culture supernatants by HPLC. Fibroblasts, A-22 arachnoidea, HK-2351 scalp, T-2346 meningeom and HeLa cervical carcinoma cells but not HL-60 promyelocytic leukaemia cells were found to degrade tryptophan upon induction by interferon-gamma. Tryptophan is converted to kynurenine by fibroblasts, A-22 arachnoidea and HK-2351 scalp cells and to kynurenine and anthranilic acid by HeLa cervical carcinoma and T-2346 meningeom cells. Kynurenine and anthranilic acid always make up more than 82% of the tryptophan degraded. None of these cells synthesizes 3-hydroxyanthranilic acid, 3-hydroxykynurenine, 7,8-dihydroneopterin or neopterin. Human macrophages form 3-hydroxyanthranilic acid and neopterin, but not 3-hydroxykynurenine, beside kynurenine and anthranilic acid upon activation by interferon-gamma. These data indicate that several human cells can be induced by interferon-gamma to degrade tryptophan. The interferon-gamma induced synthesis of 3-hydroxyanthranilic acid and neopterin, however, appears to be restricted to human macrophages. A hypothesis explaining these findings is presented.

Biopterins↗
PubMed1991

Development of affinity labeling agents based on nonsteroidal anti-inflammatory drugs: labeling of the nonsteroidal anti-inflammatory drug binding site of 3 alpha-hydroxysteroid dehydrogenase.

Nonsteroidal anti-inflammatory drugs (NSAIDs) exert their effect by inhibiting the target enzyme cyclooxygenase (prostaglandin H2 synthase); however, little is known about the peptides comprising its NSAID binding site. Hydroxyprostaglandin dehydrogenases also bind NSAIDs, but their NSAID binding sites have not been well characterized. Using existing synthetic strategies, we have incorporated the bromoacetoxy affinity labeling moiety around the perimeter of two potent NSAIDs, indomethacin and mefenamate, a N-phenylanthranilate. The compounds synthesized were 1-(4-(bromoacetamido)benzyl)-5-methoxy-2-methylindole-3-acetic acid (1), 3-(2-(2-bromoacetoxy)ethyl)-1-(4-chlorobenzyl)-5-methoxy-2-methylindole (2), 4-(bromoacetamido)-N-(2,3-dimethylphenyl)anthranilic acid (3), N-(3-(bromoacetamido)phenyl)-anthranilic acid (4), and N-(4-(bromoacetamido)phenyl)anthranilic acid (5). To access whether these compounds have general utility in labeling NSAID binding sites, the compounds were evaluated as affinity labeling agents for 3 alpha-hydroxysteroid dehydrogenase (3 alpha-HSD) from rat liver cytosol. This enzyme displays 9-, 11-, and 15-hydroxyprostaglandin dehydrogenase activity, is inhibited potently by NSAIDs, and is homologous to bovine lung prostaglandin F synthase. Compounds 1-5 were shown to affinity label the NSAID binding site of 3 alpha-HSD. They inactivated 3 alpha-HSD through an E.I complex in a time- and concentration-dependent manner with t1/2 values ranging from seconds to hours. Ligands that compete for the active site of 3 alpha-HSD (NAD+ and indomethacin) afforded protection against inactivation, and the inactivators could demonstrate competitive kinetics against 3 alpha-hydroxysteroid substrates by forming an E.NAD+.I complex.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxysteroid Dehydrogenases↗
PubMed1990

Quinolinate-induced cortical cholinergic damage: modulation by tryptophan metabolites.

Certain products of tryptophan metabolism interact with excitatory amino acid receptors to produce or protect against excitotoxicity. In this study, the action of several tryptophan metabolites, yielded by the kynurenine pathway, on cortical cholinergic toxicity was evaluated following focal injection into the rat nucleus basalis magnocellularis (nbM). Metabolites were injected singly or in combination with a fixed dose of quinolinic acid (QUIN). Cholinergic toxicity, or protection against it, was evaluated by measurements of choline acetyltransferase (ChAT) activity or potassium-evoked release of [3H]acetylcholine [( 3H]ACh) from slices of the frontoparietal cortex, from the injected and uninjected sides. Focal injections of QUIN and 3-hydroxyanthranilic, but not kynurenic, picolinic, quinaldic or anthranilic acid, produced a dose-related decrease in ChAT activity, with QUIN being more potent. Kynurenic, picolinic, quinaldic and anthranilic acid, co-injected into the nbM with QUIN (120 nmol), produced dose-related antagonism of the neurotoxicity associated with QUIN alone. Picolinic acid also prevented the reduction in cortical [3H]ACh release induced by injections of QUIN. Kynurenic and picolinic acid produced a complete blockade of QUIN's effect on cortical ChAT activity, while quinaldic and anthranilic acid produced a partial blockade. The order of effectiveness against QUIN was kynurenic greater than picolinic greater than quinalidic or anthranilic acid. Evaluation of thin sections following Cresyl violet staining indicated that injections of QUIN produced neuronal loss and glial proliferation, while co-injections of picolinic or quinaldic acid with QUIN protected neurons. These findings show that several tryptophan metabolites have the potential to either produce or antagonize cholinergic toxicity.(ABSTRACT TRUNCATED AT 250 WORDS)

3-Hydroxyanthranilic Acid↗
PubMed1975

Tryptophan catabolism in Bacillus megaterium.

Bacillus megaterium grows in a medium containing L-tryptophan as the sole carbon, nitrogen, and energy source. Kynurenine, anthranilic acid, and catechol are metabolic intermediates, suggesting that this organism used the anthranilic acid pathway for tryptophan degradation. Cells that grow on L-tryptophan oxidize kynurenine, alanine, and anthranilic acid and the presence of tryptophan oxygenase (EC 1.13.1.12), kynureninase (EC 3.7.1.3), and catechol oxygenase (EC 1.13.1.1) in cell extracts provide additional evidence for the degradative pathway in B. megaterium. Tryptophan oxygenase is inhibited by sodium azide, potassium cyanide, and hydroxylamine, indicating that the enzyme has a functional heme group. D-Tryptophan is not a substrate for tryptophan oxygenase, and the D-isomer does not inhibit this enzyme. Formamidase (EC 3.5.1.9) and anthranilate hydroxylase are not detectable in extracts. Tryptophan catabolism is inducible in B megaterium and is subject to catabolite repression by glucose and glutamate. Arginine does not cause repression, and kynurenine induces both tryptophan oxygenase and kynureninase.

Alanine↗
PubMed2002

Effects of commercial processing on levels of antioxidants in oats (Avena sativa L.).

The effects of various commercial hydrothermal processes (steaming, autoclaving, and drum drying) on levels of selected oat antioxidants were investigated. Steaming and flaking of dehulled oat groats resulted in moderate losses of tocotrienols, caffeic acid, and the avenanthramide Bp (N-(4'-hydroxy)-(E)-cinnamoyl-5-hydroxy-anthranilic acid), while ferulic acid and vanillin increased. The tocopherols and the avenanthramides Bc (N-(3',4'-dihydroxy-(E)-cinnamoyl-5-hydroxy-anthranilic acid) and Bf (N-(4'-hydroxy-3'-methoxy)-(E)-cinnamoyl-5-hydroxy-anthranilic acid) were not affected by steaming. Autoclaving of grains (including the hulls) caused increased levels of all tocopherols and tocotrienols analyzed except beta-tocotrienol, which was not affected. Vanillin and ferulic and p-coumaric acids also increased, whereas the avenanthramides decreased, and caffeic acid was almost completely eliminated. Drum drying of steamed rolled oats resulted in an almost complete loss of tocopherols and tocotrienols, as well as a large decrease in total cinnamic acids and avenanthramides. The same process applied to wholemeal made from groats from autoclaved grains resulted in less pronounced losses, especially for the avenanthramides which were not significantly affected.

Antioxidants↗
PubMed1982

The preferred route of kynurenine metabolism in the rat.

It has been suggested (Ueda, T., Otsuka, H. and Goda, K. (1978) J. Biochem. 84, 687-696) that direct cleavage of kynurenine, catalysed by kynureninase, followed by microsomal hydroxylation of the resultant anthranilic acid, may provide an alternative to the established pathway of kynurenine metabolism that involves direct hydroxylation followed by cleavage to 3-hydroxyanthranilic acid. To test this suggestion, anthranilic acid was administered to rats; there was no increase in either the concentration of nicotinamide nucleotides in the liver or the urinary excretion of N1-methyl nicotinamide. However, injection of either kynurenine or 3-hydroxyanthranilic acid did increase the concentration of nicotinamide nucleotides in the liver. The kinetics of kynurenine hydroxylase (Km = 1.8 +/- 0.6.10(-5) mol/l) and kynureninase (Km = 2.5 +/- 0.8.10(-4) mol/l, liver steady-state kynurenine = 4.9 +/- 0.9 mumol/kg) are such that the preferred route of kynurenine metabolism is probably by way of hydroxylation rather than cleavage.

Animals↗
PubMed1978

The spontaneous urinary excretion of tryptophan metabolites "via kynurenine" in women with regards to the prepuberty, sexual maturity and menopause.

High values of anthranilic acid, 3-OH-kynurenine, xanthurenic acid and 3-OH-anthranilic acid are observed in the spontaneous urinary excretion of tryptophan metabolites in girls in the prepubertal age. The highest differences are between the 3-hydroxy metabolites especially the 3-hydroxykynurenine. On the other hand, this metabolic excretion in postmenopausal women is statistically identical to that of women in sexual maturity.

Adult↗
PubMed2006

Microbial conversion of selected azo dyes and their breakdown products.

Four selected azo dyes (acid orange 6, acid orange 7, methyl orange and methyl red) were completely decolourised in the presence of anaerobic granular sludge, while only methyl red was degraded in aerobic conditions using a conventional activated sludge. Additional experiments with culture broth devoid of cells showed that anaerobic decolourisation of azo dyes was performed by extracellular reducing agents produced by anaerobic bacteria. This was further confirmed by abiotic experiments with sulphide and NADH. The presence of redox mediators such as riboflavin led to dramatic acceleration of the anaerobic biodecolourisation process. The azo dye reduction products were found to be sulphanilic acid and 4-aminoresorcinol for acid orange 6; sulphanilic acid and 1-amino-2-naphthol for acid orange 7; N,N-dimethyl-1,4-phenylenediamine and sulphanilic acid for methyl orange; and N,N-dimethyl-1,4-phenylenediamine and anthranilic acid for methyl red. Anaerobic toxicity assays showed that the azo dyes were more toxic than their breakdown products (aromatic amines), except 1-amino-2-naphthol. In the presence of activated sludge, only anthranilic acid was completely mineralised while sulphanilic acid was persistent. 4-aminoresorcinol, 1-amino-2-naphthol and N,N-dimethyl-1,4-phenylenediamine underwent autooxidation in aerobic conditions yielding coloured polymeric products. On the contrary, in the presence of granular methanogenic sludge, 4-aminoresorcinol, 1-amino-2-naphthol and anthranilic acid were quantitatively methanised, sulphanilic acid was partially (70%) mineralised while N,N-dimethyl-1,4-phenylenediamine was only demethylated producing 1,4-phenylenediamine as an end product.

Amines↗
PubMed2005

A quantitative structure-activity relationship study on some series of anthranilic acid-based matrix metalloproteinase inhibitors.

A quantitative structure-activity relationship (QSAR) study has been made on four different series of anthranilic acid-based matrix metalloproteinase (MMP) inhibitors, in which two substituted aryl rings, one bearing the hydroxamic acid moiety that binds with the zinc atom of MMPs, are joined through a bridge group of sulfonamide. The QSAR results indicate that the sulfonamide group plays a very important role in the inhibition activity of the inhibitors and that the effectiveness of this sulfonamide group can be increased by the presence at the aryl rings or at the sulfonamide nitrogen itself of nitrogen-containing or some such substituents that can increase the electronic character of the sulfonamide group. The hydrophobic character of the molecules is not found to be of any advantage; rather in most of the cases it is shown to have detrimental effect, suggesting that MMPs provide little opportunity to the inhibitors to have a any hydrophobic interactions with them. On the other hand, polarizability of the molecules has been found to be conducive to activity in some cases. Thus the inhibition mechanism seems to predominantly involve the electronic interactions between the inhibitors and the enzymes.

Matrix Metalloproteinase Inhibitors↗
PubMed2003

Neurotoxic and neurobehavioral effects of kynurenines in adult insects.

Kynurenines are endogenous metabolites of tryptophan, which are studied extensively in vertebrates with respect to their etiological role in the pathology of various neurodegenerative disorders. In insects, metabolites of the kynurenic pathway are present in peak concentrations in the hemolymph of holometabolic species during pupation and just before eclosion. Unlike in larvae, these compounds cause severe motor dysfunction in adult species. Adult flesh flies were injected with various concentrations of these endogenous toxins and the effects on motor function were assessed. For tryptophan, L-kynurenine, 3-hydroxy-kynurenine, and anthranilic acid, the effects ranged from reversible to irreversible motor dysfunction, to instant paralysis and death. 3-Hydroxy-anthranilic acid could induce a tetanus like spasm of the wings. Tryptophan, 3-hydroxykynurenine, and 3-hydroxy-anthranilic acid were toxic to primary cultures of insect neurons. It is possible that some of these metabolites have a distinct role in larvae during the apoptotic events related to neurometamorphosis.

Animals↗
PubMed1986

Non-steroidal anti-inflammatory analgesics other than salicylates.

The largest group of non-narcotic analgesics are the arylalkanoic acid derivatives, comprising derivatives of arylacetic acid, propionic acid, heteraryl acetic acid and indole acetic acid. Common to all of these drugs is their inhibition of prostaglandin biosynthesis, which contributes to their analgesic and other pharmacological properties as well as to their principal side effect, gastrointestinal irritation. Although these drugs all cause some gastric microbleeding, they do so to a lesser extent than aspirin. The arylalkanoic acid derivatives, as well as the anthranilic acid and oxicam derivatives, are peripherally acting as evidenced by their lack of activity in classical tests of central analgesic activity. After oral administration of these drugs, their peak plasma concentrations are generally attained in 1 to 3 hours; absorption is not generally influenced by food. Volume of distribution is mostly low (less than 0.2 L/kg) and protein binding is high (usually 95 to 99%). Elimination is by glucuronide formation for several of the propionic acid derivatives and generally by biotransformation for derivatives of arylacetic acid, indole and indene acetic acid, and the oxicams. The elimination half-life of the arylalkanoic acid derivatives is in most instances about 2 to 5 hours, although notable exceptions include carprofen (approximately equal to 20 h), fenbufen (10 h), naproxen (12-15 h) and sulindac (16 h for the active metabolite). The elimination half-life of indomethacin varies considerably between and within individuals. Piroxicam has the longest half-life, averaging 45 hours. The pharmacokinetic properties of the anthranilic acid derivatives (fenamates, glafenine) generally resemble those of the arylacetic acids. Few clinically significant drug interactions are associated with concomitant administration of the arylalkanoic acids or piroxicam and other drugs. Since the arylalkanoic acids are highly bound to plasma proteins (mainly albumin) there is a theoretical potential for displacement reactions with drugs that are used at plasma concentrations high enough to exceed the binding capacity of their own primary binding sites. However, such reactions have rarely been reported. Although the concomitant administration of aspirin and several of the propionic acid derivatives results in a significant decrease in the plasma concentration of the latter, the clinical significance of such interactions is uncertain and probably minimal.(ABSTRACT TRUNCATED AT 250 WORDS)

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1997

Inhibition of nitric oxide synthase expression and activity in macrophages by 3-hydroxyanthranilic acid, a tryptophan metabolite.

Indoleamine 2,3-dioxygenase (IDO) and nitric oxide synthase (NOS) type II are induced in macrophages by interferon (IFN)-gamma and lipopolysaccharide (LPS). Nitric oxide has been previously shown to inhibit IDO activity. We studied whether metabolites of tryptophan via the IDO pathway could alter NOS II activity. In RAW 264.7 cells, the phenolic antioxidant 3-hydroxyanthranilic acid (OH-AA), but not anthranilic acid, inhibited citrulline synthesis by NOS II at sub-millimolar concentrations, when added 1 h before IFN-gamma and LPS. OH-AA inhibited NOS II activity in cytosolic extracts, suggesting a direct action of OH-AA on NOS II protein. Moreover, expression of NOS II mRNA and activation of the nuclear factor kappa B (NF-kappa B) in RAW 264.7 cells were decreased by a pretreatment with OH-AA, but not anthranilic acid, before addition of IFN-gamma and LPS. This pretreatment also inhibited activation of NF-kappa B in response to TNF-alpha in lymphoblastoid J.Jhan5-1 cells. Finally, expression of a long terminal repeat of the human immunodeficiency virus (HIV-LTR)-driven luciferase reporter gene, controlled by NF-kappa B activation, was severely decreased by OH-AA or 3-hydroxykynurenine in J.Jhan5-1 cells. Other tryptophan derivatives were inactive. These data identify OH-AA as an aminophenolic tryptophan derivative inhibiting NF-kappa B activation and impairing both NOS II expression and activity in a millimolar concentration range.

3-Hydroxyanthranilic Acid↗
PubMed1977

[Studies of sulfhemoglobin formation by various drugs (3) (author's transl)].

Sulfhemoglobin (SHb) and methemoglobin (MHb) formations by various compounds were examined by single and three consecutive intraperitoneal administrations to mice. With a single administration, methemoglobinemia was induced by diphenylamine (DPA), 1-naphthylamine (NA), phenylnaphthylamine (PNA), N-(1-naphthyl) anthranilic acid (N1) and N-(1'-naphthyl)-2-aminophenylacetic acid (IG240), and was not observed with phenylanthranilic acid (PAA), N-benzoyl-N'-phenyl-2, 6-diaminobenzoic acid (BPAA), flufenamic acid (FA), mefenamic acid (MFA), N-(2-6-dichlorophenyl) anthranilic acid (CPAA), N-(2', 6'-dichlorophenyl)-2-aminophenylacetic acid (CPPA), nine derivatives of N1 and two derivatives of IG240. On the other hand, sulfhemoglobinemia, with a single administration, was found to be induced by NA. Furthermore, with three consecutive administrations, such was induced by DPA, PAA, BPAA and FA even though SHb was not demonstrated with a single administration, and was not observed with MF, CPAA, CPPA and various derivatives of N1 and IG240.

1-Naphthylamine↗
PubMed1988

Studies on some iridium(III) complexes with Schiff bases derived from amino carboxylic acids.

The reactions of iridium(III) chloride with different Schiff bases gave complexes of types [Ir(SB)3], [Ir(SB')Cl(H2O)2], [Ir(SB'')Cl2]n, [Ir(SB'' ')Cl(H2O)]n (SBH = Schiff bases derived from anthranilic acid and benzaldehyde, acetophenone, vanillin, cinnamaldehyde or m-hydroxyacetophenone; SB'H2 = Schiff bases derived from anthranilic acid and salicylaldehyde or o-hydroxyacetophenone; SB''H = Schiff bases derived from p-aminobenzoic acid and benzaldehyde, acetophenone, vanillin, cinnamaldehyde, or m-hydroxyacetophenone; SB'' 'H2 = Schiff bases derived from p-aminobenzoic acid and salicylaldehyde or o-hydroxyacetophenone). These complexes have been characterized on the basis of elemental analyses, conductance, magnetic moment, and spectral (electronic, i.r., and 1H n.m.r.) data. The electronic spectra reveals octahedral geometry for these complexes except for [Ir(SB'')Cl2]n, which is trigonal bipyramidal. The thermal behavior of these complexes has also been studied by TG, DTG, and DSC techniques. The different kinetic parameters, viz., order of reaction, activation of energy, and heat of reaction were calculated. The antifungal and antiviral activities of the complexes with Schiff bases derived from anthranilic acid have also been investigated.

4-Aminobenzoic Acid↗