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PubMed1999

Synthesis and evaluation of anthranilic acid-based transthyretin amyloid fibril inhibitors.

Eight small molecules were synthesized to evaluate the structure activity relationships (SAR) of N-substituted anthranilic acids. The molecules were synthesized by benzylation or arylation of methyl anthranilate. A light scattering-based amyloid fibril formation assay was used to evaluate potential inhibitors of transthyretin (TTR) amyloid fibril formation in vitro. The m-carboxyphenylated and o-trifluoromethylphenylated anthranilic acids are potent inhibitors that will be subjected to further SAR and structural analysis.

Amyloid↗
PubMed2003

Kynurenines and the respiratory parameters on rat heart mitochondria.

It has been shown recently that the L-kynurenine metabolite kynurenic acid lowers the efficacy of mitochondria ATP synthesis by significantly increasing state IV, and reducing respiratory control index and ADP/oxygen ratio of glutamate/malate-consuming heart mitochondria. In the present study we investigated the effect of L-tryptophan (1.25 microM to 5 mM) and other metabolites of L-kynurenine as 3-hydroxykynurenine (1.25 microM to 2.5 mM), anthranilic acid (1.25 microM to 5 mM) and 3-hydroxyanthranilic acid (1.25 microM to 5 mM) on the heart mitochondria function. Mitochondria were incubated with saturating concentrations of respiratory substrates glutamate/malate (5 mM), succinate (10 mM) or NADH (1 mM) in the presence or absence of L-tryptophan metabolites. Among tested substances, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and anthranilic acid but not tryptophan affected the respiratory parameters dose-dependently, however at a high concentration, of a micro molar range. 3-Hydroxykynurenine and 3-hydroxyanthranilic acid lowered respiratory control index and ADP/oxygen ratio in the presence of glutamate/malate and succinate but not with NADH. While, anthranilic acid reduced state III oxygen consumption rate and lowered the respiratory control index only of glutamate/malate-consuming heart mitochondria. Co-application of anthranilic acid and kynurenic acid (125 or 625 microM each) to glutamate/malate-consuming heart mitochondria caused a non-additive deterioration of the respiratory parameters determined predominantly by kynurenic acid. Accumulated data indicate that within L-tryptophan metabolites kynurenic acid is the most effective, followed by anthranilic acid, 3-hydroxykynurenine, 3-hydroxyanthranilic acid to influence the respiratory parameters of heart mitochondria. Present data allow to speculate that changes of kynurenic acid and/or anthranilic acid formation in heart tissue mitochondria due to fluctuation of L-kynurenine metabolism may be of functional importance for cardiovascular processes. On the other hand, beside the effect of 3-hydroxyanthranilic acid and 3-hydroxykynurenine on respiratory parameters, their oxidative reactivity may contribute to impairment of mitochondria function, too.

3-Hydroxyanthranilic Acid↗
PubMed1997

Purification and 1H NMR spectroscopic characterization of phase II metabolites of tolfenamic acid.

Tolfenamic acid, an anti-inflammatory drug (NSAID), is metabolized in vivo to form several oxidative metabolites which are all conjugated with beta-D-glucuronic acid. In this study, the metabolites of tolfenamic acid were identified by 1H nuclear magnetic resonance (NMR) spectroscopy in urine samples obtained on days 7 to 10 from a human volunteer after oral administration of 200 mg of the drug three times per day (steady-state plasma concentration). The metabolites of tolfenamic acid were initially concentrated by preparative solid phase extraction (PSPE) chromatography, thereby removing the endogenous polar compounds that are present in the urine. The individual metabolites were purified by preparative high performance liquid chromatography (HPLC) and then identified using 1H NMR. Both one- and two-dimensional NMR experiments were performed to identify the phase II metabolites of tolfenamic acid; the study shows the applicability of 1H NMR for the identification of drug metabolites in biological fluids. In addition to NMR analysis, two metabolites were also identified by mass spectrometry (MS). The glucuronides of the following parent compounds, N-(2-methyl-3-chlorophenyl)-anthranilic acid (T), N-(2-hydroxymethyl-3-chlorophenyl)-anthranilic acid (1), N-(2-hydroxymethyl-3-chloro-4-hydroxyphenyl)-anthranilic acid (2), N-(2-formyl-3-chlorophenyl) anthranilic acid (3), N-(2-methyl-3-chloro-4-hydroxyphenyl)-anthranilic acid (4), N-(2-methyl-3-chloro-5-hydroxyphenyl)-anthranilic acid (5), N-(2-carboxy-3-chlorophenyl)-anthranilic acid (6), N-(2-hydroxymethyl-3-chlorophenyl)-4-hydroxy-anthranilic acid (7), N-(2-methyl-3-chlorophenyl)-5-hydroxy-anthranilic acid (8), N-(2-methyl-3-chloro-4-metoxyphenyl)-anthranilic acid (9), N-(2-methyl-3-chlorophenyl)-4-hydroxy-anthranilic acid (10), and N-(2-methyl-4-hydroxyphenyl)-anthranilic acid (11) were identified. The phase II metabolites (5-11) had not previously been identified in urine from humans administered tolfenamic acid. The phase I metabolites of the glucuronides 7, 8, 10, and 11 were identified here for the first time. An HPLC method was developed that simultaneously separates all the phase II metabolites identified as well as some phase I metabolites in urine samples obtained after intake of tolfenamic acid.

Anti-Inflammatory Agents, Non-Steroidal↗
PubMed1982

Synthesis and biological activity of certain derivatives of 2,4-dioxo-1,2,3,4-tetrahydroquinazoline. Part 2.

The synthesis of 6-bromo-1-ethyl-2,4-dioxo-1,2,3,4-tetrahydroquinazoline, its benzoyl and its benzyl derivatives is described. The unreported 5-bromo-N-phenyl-anthranilic acid was synthesized from anthranilic acid adopting a procedure, which involved a novel synthesis of 2,5-dibromobenzoic acid. Direct bromination of N-phenylanthranilic acid and N-p-tolyl-anthranilic acid afforded the tribromo-and dibromoderivatives respectively.

Animals↗
PubMed1978

The effect of environment on tryptophan metabolism "via kynurenine" in oral contraceptives users.

We have studied tryptophan metabolism "via kynurenine" in women who were oral contraceptives users, living in two different egyptian environments: in the city of Alexandria or in a rural area near Tanta and, in comparison, in control groups of women living in the same environments but who were not contraceptives users. In the non contraceptives users of Tanta we have registered a higher elimination of some metabolites (anthranilic acid, kynurenic acid, xanthurenic acid and 3-OH-anthranilic acid) which might be related to the way of life and environment. The pattern of the kynurenine pathway metabolites of the contraceptives users (studied 1, 3 and 12 months after contraceptives administration) shows some differences with respect to the controls, both in the spontaneous elimination and in that after tryptophan load. These differences are especially evident for anthranilic acid glucuronide, kynurenine and kynurenic, anthranilic and xanthurenic acids. Some differences may be observed after 1 month of contraceptives administration. The effect of tryptophan oral load is superimposed on those of environment and contraceptives use; in the spontaneous elimination of tryptophan metabolites an accomodation to the contraceptives administration is evident. The discrepancies between some of our results and those of the literature might be related to the influence of environmental factors and of the way of life.

Aminohippuric Acids↗
PubMed2005

Synthesis and evaluation of new quinazolone derivatives of nalidixic acid as potential antibacterial and antifungal agents.

In continuation of our work on synthesis of biheterocycles carrying the biodynamic heterocyclic systems at position 3, a series of new nalidixic acid derivatives having quinazolones moiety were synthesised to achieve enhanced biological activity and wide spectrum of activity. Nalidixic acid was first converted into its acid chloride using thionyl chloride as an acylating agent at laboratory temperature. Later it was converted to methyl ester. Nalidixoyl chloride formed vigorously reacts with methanol to give a methyl ester of nalidixic acid. The ester on addition of hydrazine hydrate furnished nalidixic acid hydrazide. Appropriate anthranilic acid was refluxed with acetic anhydride to form Benzoxazine/Acetanthranil. 5-iodo-derivative of anthranilic acid was prepared and also utilised to obtain 6-iodo-Benzoxazine/Acetanthranil. Also, 6-nitro-Benzoxazine/Acetanthranil was obtained by nitration of acetanthranil using conc. H(2)SO(4) and fuming HNO(3). Equimolar proportions of the appropriate synthesised acetanthranils and nalidixic acid hydrazide in the presence of ethanol were refluxed to synthesise quinazolones. Elemental analysis and IR spectra confirmed nalidixic acid hydrazide formation. The structures of the compounds obtained have been established on the basis of Spectral (IR, (1)H NMR and mass) data. The current study also involves in vitro antimicrobial screening (using Agar dilution and Punch well diffusion method) of synthesised quinazolone derivatives bearing nalidixic acid moiety on randomly collected microbial strains. The derivatives Ga (NAH), Gb (QN) and Gd (NiQNA) showed marked inhibitory activity against enteric pathogen like Aeromonas hydrophila, a causative agent of diarrhoea in both children as well as adults. Among the respiratory pathogens included in study, derivative Gd (NiQNA) was found to be active against Streptococcus pyogenes. No significant inhibitory activity was seen by any of synthesised derivatives against Coagulase negative Staphylococcus. Derivative Ga (NAH) was found to show very high activity against the Candida colonies and derivative Gd (NiQNA) was also found to exhibit inhibitory activity against Candida albicans; a normal flora of the human body which plays an important role in causing opportunistic infections in immunocompromised hosts. Proteus vulgaris, a gram-negative bacteria included in our study was found to be inhibited by derivative Gb (QN).

Adult↗
PubMed2006

Kynurenine pathway metabolism in patients with osteoporosis after 2 years of drug treatment.

1. Metabolism of tryptophan along the oxidative pathway via kynurenine results in the production of quinolinic acid and kynurenic acid, which can act on glutamate receptors in peripheral tissues. We have now measured the concentrations of kynurenine pathway metabolites in the plasma of patients with osteoporosis before treatment with drugs, throughout and after 2 years of treatment with the drugs raloxifene or etidronate. Oxidative stress was assessed by measuring levels of the lipid peroxidation products malondialdehyde and 4-hydroxynonenal. Kynurenines were analysed by HPLC. Bone density was measured using dual-energy X-ray absorptiometry scans. 2. Patients with osteoporosis showed significantly lower baseline levels of 3-hydroxyanthranilic acid compared with healthy controls, but significantly higher levels of anthranilic acid and lipid peroxidation products. After 2 years treatment with etidronate and calcium, we observed significant therapeutic responses quantified by bone densitometric scanning. Significant improvements were not seen in patients treated with raloxifene. 3. In parallel, the levels of 3-hydroxyanthranilic acid, anthranilic acid and lipid peroxidation products were restored to control values by both drug treatments studied and tryptophan levels were increased significantly compared with baseline values. 4. The results suggest that tryptophan metabolism is altered in osteoporosis in a manner that could contribute to the oxidative stress and, thus, to progress of the disease. The oxidative metabolism of tryptophan (the kynurenine pathway) could represent a novel target for the development of new drugs for the treatment of osteoporosis. In addition, we noted that etidronate is a more effective drug than raloxifene, but that the simultaneous use of non-steroidal anti-inflammatory drugs may reduce the efficacy of etidronate.

3-Hydroxyanthranilic Acid↗
PubMed1977

Absorption, distribution and metabolic fate of 2,3-dihydro-9H-isoxazolo-[3,2-b]quinazolin-9-one (W2429).

After oral administration to rats, mice, beagle dogs and human volunteers, 2,3-dihydro-9H-isoxazolo [3,2-b]-quinazolin-9-one (W 2429) is readily absorbed. The initial half-lives for the elimination from the circulation of these four species are about 240, 20, 40 and 120 min, respectively. Studies in the rat, using 9-14C-W-2429 and 3a-14C-W-2429, showed that more than half of the radioactivity is excreted in the urine. The major urinary metabolite in the rat and dog is a conjugated form of W-2429. Metabolic cleavage of the pyrimidone ring of W-2429 yields 3-(o-carboxyphenylimino)isoxazolidine, which in turn is converted to anthranilic and malonic acids. Anthranilic acid is acetylated and hydroxylated, and these products are excreted partly in the form of their glycine and glucuronic acid conjugates. The isoxazole ring of W-2429 is also dehydrogenated during metabolism to yield 9H-isoxanzolo-[3,2-b]quinazolin-9-one.

Administration, Oral↗
PubMed1985

[Etiology of bladder cancer].

Multiple agents have been suggested as urinary bladder carcinogens. Of these, certain aromatic amines and some tryptophan metabolites (Anthranilic acid, 3 hydroxy Anthranilic acid) have been proved to be carcinogenic. Others are suggested but are not conclusively proved as carcinogenic agents. Various animal species have been used as experimental models for the study of induction of cancer of the bladder and substantial progress has been made in the search for etiologic factors and pathogenesis of bladder tumors. A carcinogenic model of cancer bladder induction is proposed. However, knowledge of the tumorigenesis of cancer of the bladder is still limited and fragmentary. It appears, however, that Tryptophan dysmetabolism play a major role in this field and future experimental and epidemiologic studies should take this fact into consideration.

Animals↗
PubMed1980

Metabolism of tryptophan by Pseudomonas aureofaciens and its relationship to pyrrolnitrin biosynthesis.

Studies on the metabolism of tryptophan in Pseudomonas aureofaciens ATCC 15926 revealed different metabolic routes for the L- and D-isomer besides the biosynthetic pathway for pyrrolnitrin synthesis. L-Tryptophan catabolism follows the aromatic route via anthranilic acid. Tryptophan 2,3-dioxygenase were induced by L-tryptophan. Kynureninase and anthranilate 1,2-dioxygenase were induced by L-tryptophan, L-kynurenine and anthranilic acid. Anthranilate 1,2-dioxygenase was absent from a mutant strain of P. aureofaciens ATCC 19526 which produced about 30-fold increased amounts of pyrrolnitrin. The Km values of tryptophan 2,3-dioxygenase and kynureninase did not differ substantially between the two strains. Kynurenine 3-monooxygenase, 3-hydroxyanthranilate 3,4-dioxygenase, tryptophanase and indolyl-3-alkane alpha-hydroxylase activities were not detected. D- and L-tryptophan were converted to indole-3-acetic acid. This additional catabolic pathway was well as tryptophan racemase activity was constitutive and present in both strains.

Antifungal Agents↗
PubMed1976

[Metabolic products of microorganisms. 156. Synthesis and biosynthesis of substituted tryptanthrins (author's transl)].

Candida lipolytica synthesizes the antibiotic tryptanthrin from 1 mole tryptophan and 1 mole anthranilic acid. When feeding tryptophan and substituted anthranilic acids, or substituted tryptophans and anthranilic acid, we could isolate and identify the expected derivatives of tryptanthrin. The enzymes of the biosynthesis of tryptanthrin, with the exception of bromotryptophan, had no specifity for these substrates. In addition to these experiments substituted tryptanthrines were chemically synthesized. We checked them for antibiotic action; the halogen compounds turned out to be especially effective.

Anti-Bacterial Agents↗
PubMed1995

Relationship between serum tryptophan and tryptophan metabolite levels after tryptophan ingestion in normal subjects and age-related cataract patients.

1. Cataract is the single major cause of blindness worldwide; however, the reasons for the development of this condition remain unknown. It has been suggested that the essential amino acid tryptophan may be implicated in the aetiology but definitive evidence has been lacking. 2. The serum levels of tryptophan and seven of its metabolites have been measured in both cataract patients and control subjects, after administration of tryptophan, in order to determine the typical response profile and to discover whether differences could be found in tryptophan metabolism in the two groups. 3. Tryptophan, kynurenine, kynurenic acid, xanthurenic acid, 3-hydroxyanthranilic acid, 5-hydroxyanthranilic acid, 5-hydroxytryptophan and anthranilic acid were measured by HPLC with dual electrochemical and programmable wavelength fluorescence detection. Fasting cataract patients (n = 42) and control subjects (n = 37) were given an oral dose of L-tryptophan and sera were sampled at 0, 1, 2, 4 and 6 h. 4. Statistically significant differences in the distribution of data between the two groups were observed. The responses of kynurenine and 5-hydroxyanthranilic acid were higher in cataract patients, but those of kynurenic acid and total tryptophan were lower than in control subjects. No statistically significant differences in free tryptophan, anthranilic acid, 3-hydroxyanthranilic acid, xanthurenic acid or 5-hydroxytryptophan levels were noted. 5. We conclude that there is a major subgroup of age-related cataract patients with a dysfunction in the metabolism of tryptophan. This may be related to the onset of cataract. The mechanism remains to be established but may operate via the action of tryptophan metabolites, such as 5-hydroxyanthranilic acid, which become reactive towards protein upon oxidation.

Age Factors↗
PubMed1995

Purification of recombinant human rhinovirus 14 3C protease expressed in Escherichia coli.

A gene encoding the human rhinovirus 14 (HRV14) sequence for expression of the viral polypeptide protein delta 3ABC was inserted into a plasmid driven by the heat-inducible bacteriophage lambda PL promoter. The coding sequence was also inserted into a pET vector for expression in the T7 system to produce 13C, 15N-labeled protein. The expressed HRV14 3C protease (3Cpro) autocatalytically cleaved itself from the polyprotein delta 3ABC, and the mature HRV14 3Cpro partitioned predominantly, in the case of the T7 system, in the insoluble fraction and exclusively, in the case of the PL system, in the insoluble fraction. The insoluble HRV14 3Cpro was solubilized in urea and purified using anion- and cation-exchange chromatography. The protease was refolded/activated and further purified using a size-exclusion column. HRV14 3Cpro was purified to > 90% homogeneity as shown by SDS-PAGE and to 95% by HPLC. A continuous fluorescence assay was developed which utilized an intramolecularly quenched 9-amino-acid substrate. The substrate anthranilic acid (Anc)-Thr-Leu-Phe-Gln-Gly-Pro-Val-(p-NO2)-Phe-Lys mimicked the natural 2C/3A cleavage site (Thr-Leu-Phe-Gln-Gly-Pro-Val-Tyr-Phe) using an N-terminal anthranilic acid donor group on one side of the scissile bond (Gln/Gly) and a p-NO2-Phe acceptor group at the P4 position. Measured by the fluorescence assay, HRV14 3Cpro had a Km of 300 microM for the substrate.

3C Viral Proteases↗
PubMed1978

Regulative influence of o-aminobenzoic acid on the biosynthesis of nourseothricin in cultures of Streptomyces noursei JA 3890b. III. Change of redox state of nicotinamide-adenine-dinucleotides in the presence of aminobenzoic acids.

o-Aminobenzoic acid (OABA, anthranilic acid) and related compounds which are known to stimulate the biosynthesis of streptothricin-type antibiotic nourseothricin by Streptomyces noursei JA 3890b were found to increase strongly the NADH/NAD+ ratio in growing mycelium of this strain suggesting that these effectors are capable of interfering with the function of the respiratory chain. In parallel, a complex shift of metabolism was induced shown by simultaneous alteration of mycelial activities of alanine dehydrogenase, glutamine synthetase, and glutamate dehydrogenase. These changes may be responsible for the observed delay of amino acid catabolism and may improve the precursor supply of the secondary metabolism.

Alanine↗
PubMed1979

Effect of nonsteroidal anti-inflammatory and other pharmacological agents on tuberculin reaction.

Nonsteroidal anti-inflammatory and other pharmacological agents were tested in the efferent arc of the tuberculin skin reaction in the guinea pig. A low but significant inhibition was produced by the acidic anti-inflammatory agents, including the arylalkanoic acids, the anthranilic acids, indomethacin, and phenylbutazone. Some nonacidic anti-inflammatory agents also were inhibitory; benzydamine caused a high inhibition. Except for methotrexate, the antineoplastic--antimetabolite agents were not potent inhibitors. Inhibition without toxicity was produced by the coumarin anticoagulants, the diuretics, chloroquine, tilorone, and the following immunoregulators: antithymocyte gamma-globulin, cyclophosphamide, and penicillamine. Levamisole, colchicine, heparin, and niridazole were inhibitory but produced lethality either at or above the effective dose.

Animals↗
PubMed1981

The effect of pyrazines on the metabolism of tryptophan and nicotinamide adenine dinucleotide in the rat. Evidence of the formation of a potent inhibitor of aminocarboxy-muconate-semialdehyde decarboxylase from pyrazinamide.

The intraperitoneal or oral administration of pyrazinamide and pyrazinoic acid (pyrazine 2-carboxylic acid) resulted in a marked increase of the NAD content in rat liver. The injections of pyrazine and pyrazine 2,3-dicarboxylic acid exhibited no significant effect on the hepatic NAD content. The boiled extract obtained from liver and kidney of rat injected with either pyrazinamide or pyrazinoic acid exhibited a potent inhibitory effect on the aminocarboxymuconate-semialdehyde decarboxylase (EC 4.1.1.45) activity in either lier or kidney, although pyrazinamide or pyrazinoic acid per se did not inhibit the enzyme activity. The unknown inhibitor of aminocarboxymuconate-semialdehyde decarboxylase was dialysable and heat-stable, and mostly excreted in urine by 6 and 12 h after injected of pyrazinoic acid and pyrazinamide, respectively. Pyrazine 2,3-dicarboxylic acid, pyrazine, nicotinamide, nicotinic acid, tryptophan, anthranilic acid, 5-hydroxyanthranilic acid and quinolinic acid exhibited no significant effect on the aminocarboxymuconate-semialdehyde decarboxylase activity in liver and kidney at the concentration of 1 mM in the reaction mixture. The expired 14CO2 from L-[benzen ring-U-14C]tryptophan was markedly decreased by the pyrazinamide injection, while the urinary excretion of 14C-labeled metabolites from L-tryptophan, mainly quinolinic acid, was markedly increased. These results suggest that the glutarate pathway of L-tryptophan was strongly inhibited by the inhibitor produced after the administration of pyrazinoic acid and pyrazinamide. Pyrazinamide but not pyrazinoic acid also exhibited a significant inhibition of the nuclear enzyme poly(ADP-ribose) synthetase in rat liver.

Animals↗
PubMed1985

Incorporation of chorismic acid and 4-aminobenzoic acid into the 4-hydroxyaniline moiety of N-(gamma-L-glutamyl)-4-hydroxyaniline in Agaricus bisporus.

Agaricus bisporus contains the unique aniline derivative, N-(gamma-L-glutamyl)-4-hydroxyaniline. 14C-labelled chorismic acid was quantitatively incorporated into the 4-hydroxyaniline moiety of this aniline derivative, whereas 14C-labelled prephenic acid and anthranilic acid were not incorporated into 4-hydroxyaniline. These observations indicate the branch point of the biosynthetic route of 4-hydroxyaniline in the shikimic acid pathway to be chorismic acid. Moreover, 4-aminobenzoic acid proved to be an effective precursor of 4-hydroxyaniline.

4-Aminobenzoic Acid↗