ISCHEMIC ARM PAIN AND THE NONNARCOTIC ANALGESIC MEFENAMIC ACID, N-(2,3-XYLYL)ANTHRANILIC ACID.
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Analgesics↗
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Bioassay of anthranilic acid for possible carcinogenicity.
A bioassay of anthranilic acid for possible carcinogenicity was conducted by administering the test chemical in feed to Fischer 344 rats and B6C3F1 mice. Groups of 35 rats and 35 mice of each sex were administered anthranilic acid at one of the following doses, either 15,000 or 30,000 ppm for the rats, and either 25,000 or 50,000 ppm for the mice, 5 days per week for 78 weeks, then observed for an additional 26-27 weeks. Matched controls consisted of groups of 15 rats and 15 mice of each sex; pooled controls, used for statistical evaluation, consisted of the matched controls combined with 15 untreated male and 15 untreated female animals of each species from a similar bioassay of another test chemical Except for the matched-control male mice, all surviving animals in the study were killed at 104-106 weeks. Half of the matched-control male mice, which were accidentally killed at week 12, were excluded from the report; the remaining matched-control males died by week 94. Mean body weights of the low-and high-dose male and high-dose female rats were lower than those of the corresponding matched controls for the duration of the study. The weights of the low-dose females were similar to those of the matched controls for the first 45 weeks, after which they declined slightly. The weights of the low-dose male mice were similar to those of the matched controls, while those of the high-dose males and of the low-and high-dose females were slightly lower. Survival of both treated and matched-control groups of rats of both sexes was high; survival of treated mice of both sexes and of female matched controls, although lower than that of the rats, was sufficient for meaningful statistical analyses of the incidences of tumors. In rats, a variety of neoplasms were observed in both treated and control animals. Few malignant tumors were found, and no tumors occurred in treated animals in statistically significant incidences when compared with control animals. In mice, a variety of neoplasms were observed in both treated and control animals. These neoplasms are not uncommon in this strain of mouse, and none occurred in treated animals in statistically significant incidences when compared with control animals. It is concluded that under the conditions of this bioassay, anthranilic acid was not carcinogenic for either Fischer 344 rats or B6C3F1 mice.
Journal Article↗
Newer N-substituted anthranilic acid derivatives as potent anti-inflammatory agents.
The new 5-bromo-N-[2'-amino(1"-acetyl-5"substitutedaryl-2"-pyrazolin-3"-yl)-1',3',4'-oxadiazol-5'-ylmethyl]anthranilic acids 7a-7e and N-[2'-amino-(1"-acetyl-5"-substiutedaryl-2"-pyrazolin-3"-yl)-1',3',4'-thiadiazol-5'-ylmethyl]anthranilic acids 6'a-6'c have been synthesised from 5-bromo-N-(2'-aminosubstituedbenzylideneacetyl-1',3',4'-oxadiazol-5'-ylmethyl)anthranilic acids 6a-6e and N-(2'-aminosubstitutedbenzylideneacetyl-1',3',4'-thiadiazol-5'-ylmethyl)anthranilic acids 5'a-5'e, respectively. All these compounds have been screened in vivo for their anti-inflammatory and acute toxicity. Compounds 7b and 6'b were found to be potent member of this series, which showed 50.66 and 47.56%, respectively, inflammation inhibitory activity at a dose of 50 mg kg(-1) p.o., while standard drug, phenylbutazone, exhibited 45.52% anti-inflammatory activity at the same dose. However, 5-bromo-N-[2'-amino-[1"-acety1-5"-(para-methoxyphenyl)-2"-pyrazolin-3"-yl]-1',3',4'-oxidiazol-5'-ylmethyl]anthranilic acid (7b) was found to be the most active and less ulcerogcnic compound than the standard drag mid rest of the compounds of this series. The structures of these compounds have been established by IR, 1H-NMR spectroscopic data and elemental analyses.
Administration, Oral↗
Synthesis and antimicrobial activity of some anthranilic acid derivatives.
The synthesis of eight derivatives of anthranilic acid is described. Investigation of their antimicrobial activity showed that four of the compounds, viz; anthranilohydrazide, 3,4-dihydro-4-oxo-1,2,3-benzotriazine, triazine-beta-naphthol adduct and N-phenyl anthranilic acid showed significant antibacterial activity. None of the compounds showed any noticeable antifungal effect.
Anti-Bacterial Agents↗
Interactions of a beta-dipeptide with monovalent metal cations: crystal structures of (anthranoyl)anthranilic acid and its lithium, sodium and thallium salts.
X-ray crystal structure analyses have been performed on the beta-dipeptide (anthranoyl)anthranilic acid [HAnthAnthOH] and its lithium, sodium and thallium salts [HAnthAnthOM] to give a first set of data for this representative model ligand. Crystals of the beta-dipeptide are orthorhombic, space group Pca2(1). The unit cell contains two molecules of (anthranoyl)anthranilic acid which form a dimer via hydrogen bonds. The components of the beta-dipeptide are rotated into the trans-conformation which allows for internal hydrogen bonds. The pKS value of (anthranoyl)anthranilic acid (9.80+/-0.14) shows a slight decrease as compared to anthranilic acid; the metal salts can therefore be prepared by direct neutralization of the beta-dipeptide with metal hydroxides or carbonates. The alkali compounds crystallize as the trihydrates [HAnthAnthOM(H2O)3, M=Li, Na] in the triclinic space group p1. Both metal ions show a clear preference for water molecules over the (anthranoyl)anthranilate anions as ligands in their coordination spheres. As a consequence, the [HAnthAnthO]- anions are only partially involved in metal complexation. The cell plots of both compounds exhibit a stacking with an alternation of oppositely charged layers. The negatively charged layers are composed exclusively of (anthranoyl)anthranilate anions. The thallium compound crystallizes as the hemihydrate [HAnthAnthOTl(H2O)0.5] in the monoclinic space group C2/c. In the dinuclear units, the thallium ions accommodate one nitrogen and four oxygen atoms of the anions in their coordination sphere and in addition entertain weak Tl-arene contacts. In contrast to the alkali compounds, the water molecules are not involved in metal complexation, but contribute to a network of hydrogen bonding.
Cations, Monovalent↗
Oral antipyretic therapy: evaluation of the N-aryl-anthranilic acid derivatives mefenamic acid, tolfenamic acid and flufenamic acid.
The antipyretic activity of three N-aryl-anthranilic acid derivatives, mefenamic acid, tolfenamic acid and flufenamic acid, was compared and their optimal antipyretic dose determined in a trial in 87 children (aged 5 months to 15 years), who suffered from infections and fever exceeding 38.5 degrees C. Tolfenamic acid proved to be the most potent antipyretic agent of the three drugs; it was eight times more powerful than mefenamic acid and three times more powerful than flufenamic acid. The optimal antipyretic doses were: mefenamic acid 4 mg/kg, tolfenamic acid 0.5 mg/kg and flufenamic acid 1.5 mg/kg. It is evident that the antipyretic activity of these anthranilic acid derivatives is even greater than their antirheumatic effect, the difference being most noticeable in the case of tolfenamic acid.
Adolescent↗
Species differences in L-tryptophan-kynurenine pathway metabolism: quantification of anthranilic acid and its related enzymes.
Anthranilic acid (AA) has attracted considerable attention as one of the L-tryptophan-kynurenine pathway metabolites in the central nervous system. In this study, a highly sensitive and accurate method for the quantification of AA has been developed using reversed-phase high-performance liquid chromatography with electrochemical detection. Serum and cerebrospinal fluid (CSF) AA concentrations in different animal species were measured. CSF AA concentrations in rabbits were 1.1 +/- 0.1 nmol/liter, which were 5. 7-33.0 times lower than those in other species studied. Serum AA concentrations, however, were slightly higher in rabbits than in other species. In contrast, the concentrations of L-kynurenine (L-KYN) in both serum and CSF were substantially higher in rabbits than in other species. Tissue kynurenine pathway enzymes, indoleamine 2,3-dioxygenase (IDO), tryptophan 2,3-dioxygenase, kynurenine 3-hydroxylase, and kynureninase were determined in rabbits, rats, gerbils, and mice. These enzymes varied among species, especially lung IDO activities in rabbits were 146-516 times higher than those found in other species, but rabbit liver kynurenine 3-hydroxylase activities were lower by one order of magnitude than those of the other species tested. Furthermore, brain kynurenine 3-hydroxylasae activities were 12.3-23.2 times higher in gerbils than those in the other species tested. In addition, AA concentrations in serum following intravenous administration of L-KYN (5 mg/kg) were also measured in rabbits. AA levels peaked sharply within 5 min after administration and decreased in a time-dependent manner. At 5 min after administration, CSF L-KYN and AA concentrations were also increased by 1.76- and 2.56-fold, respectively, compared with basal levels. Increased AA concentrations in CSF following L-KYN administration may reflect the entry of AA into the CSF after conversion to AA in systemic tissue and/or the local synthesis of AA from L-KYN in the CNS.
Animals↗
The inhibition mechanism of histamine release by N-(3,4-dimethoxycinnamoyl) anthranilic acid.
N-(3,4-Dimethoxycinnamoyl) anthranilic acid (N-5') is an inhibitor of IgE-mediated histamine release from mast cells. To elucidate inhibition mechanism, effects of N-5' were examined under various conditions using peritoneal exudate cells and isolated mast cells of rats. N-5' inhibited histamine release induced by antigen, ionophore A23187, ATP, dextran and phospholipase A2. But the release induced by compound 48/80 or ionophore X537A was not inhibited. Influx of Ca++ into mast cells and ATP consumption were inhibited. Based on these results, it is presumed that N-5' interferes with the energy-requiring system and/or Ca++ influx resulting in the inhibition of histamine release.
Adenine Nucleotides↗
Accumulation of anthranilic acid and N-glucosylanthranilic acid by a Corynebacterium glutamicum mutant resistant to DL-serine hydroxamate.
During a study on the effect of DL-serine hydroxamate on Corynebacterium glutamicum (JCM1318, a wild strain), a mutant resistant to the drug, strain TO3002, was isolated. This mutant accumulated five Ehrlich's reagent positive fluorescent substances in the culture medium. Two major and one minor fluorescent products were isolated by preparative high-performance liquid chromatography following charcoal column chromatography from the culture supernatant. One major product was identified as anthranilic acid whose molecular ion was confirmed to be 137 by a measurement of liquid chromatography-mass spectrometry (LC-MS), and NMR spectrum coincided with that of anthranilic acid. LC-MS spectra of another major and the minor product showed that they had the same molecular weight of 299. This major product was supported to be N-glucosylanthranilic acid (N-o-carboxyphenyl-1-beta-glucosylamine) by two-dimensional (1)H and (13)C NMR analyses. The minor product was speculated to be an Amadori compound derived from N-glucosylanthranilic acid. N-Glucosylanthranilic acid accumulated in the early phase, then decreased in the late phase of the culture. In contrast, the accumulation of anthranilic acid increased remarkably in the late phase of the fermentation. Based on this phenomenon, it was assumed that N-glucosylanthranilic acid once accumulated was decomposed to form anthranilic acid, at least in large part, with the progress of fermentation. The strain TO3002 showed a leaky requirement for L-tryptophan or indole (but did not for anthranilic acid) and resistance to DL-serine hydroxamate.
Journal Article↗
The metabolism of [carboxyl-14C]anthranilic acid. I. The incorporation of radioactivity into NAD+ and NADP+.
A new pathway of NAD+ synthesis from anthranilic acid was found in the livers of rats. Starting from [carboxyl-14C]anthranilic acid, radioactive NAD+ and NADP+ were produced as judged by Dowex-1 X 8-formate column chromatography followed by radiochromatography. Several intermediate compounds, such as quinolinic acid, nicotinic acid mononucleotide, and nicotinic acid adenine dinucleotide were also identified with the aid of various chromatographic techniques. In the experiments with liver microsomal hydroxylation systems, anthranilic acid was converted into not only 5-hydroxyanthranilic acid but also 3-hydroxyanthranilic acid.
Animals↗
Study of a corn (Zea mays L.) mutant (blue fluorescent-1) which accumulates anthranilic acid and its beta-glucoside.
A corn (Zea mays L.) mutant, blue fluorescent-1 (bf), is described that shows ultraviolet light induced blue fluorescence in young seedling leaves if homozygous for the mutant gene, and in anthers if either homozygous or heterozygous. The blue fluorescent compounds were extracted with acetone and separated by paper chromatography. Anthranilic acid was present and the beta-glucoside was also identified by paper chromatography and beta-glucosdase and acid treatment. A third major fluorescent compound was not identified, but it was convertible to anthranilic acid by acid treatment. Anthranilate synthetase from mutant plants was 3-40 times more active and was also more resistant to feedback inhibition by tryptophan than was the enzyme from normal plants. The high activity and feedback resistance would both lead to anthranilate accumulation. Anthranilate-phosphoribosylpyrophosphate phosphoribosyltransferase (PR transferase), the enzyme which usually utilizes anthranilate in the tryptophan pathway, was inhibited by the beta-glucoside of anthranilic acid in a noncompetitive manner and showed very little activity in the mutant plant extract. This inhibition of the enzyme which utilizes anthranilate would also lead to accumulation. Apparently the oversynthesis of anthranilate leads to the formation of the beta-glucoside, which inhibits anthranilate utilization. The fluorescent compounds are absent in seed, but form on germination. The levels decrease with age after 35 days postgermination, but are still present in leaves during grain filling.
Anthranilate Phosphoribosyltransferase↗
Presence of 3-hydroxyanthranilic acid in rat tissues and evidence for its production from anthranilic acid in the brain.
As assessed by HPLC with electrochemical detection, 3-hydroxyanthranilic acid (3-HANA) was found to be present in the rat brain and peripheral organs. The highest concentrations were measured in the kidney (86 fmol/mg of tissue) and spleen (56 fmol/mg of tissue), whereas the adrenal gland, liver, heart, and several forebrain areas (hippocampus, striatum, parietal cortex, thalamus, amygdala/pyriform cortex, and frontal cortex) contained less 3-HANA (between 15 and 22 fmol/mg of tissue). Slightly lower concentrations of 3-HANA were found in the brainstem and the cerebellum. The metabolic disposition of 3-HANA was examined in tissue slices which were incubated in Krebs-Ringer buffer at 37 degrees C in vitro. Incubation for up to 2 h did not affect 3-HANA concentration in brain tissue. However, inhibition of 3-HANA degradation by the specific 3-hydroxyanthranilic acid oxygenase blocker 4-chloro-3-hydroxyanthranilic acid (4-Cl-3-HANA; 10 microM) resulted in a rapid (within 2.5 min) doubling of 3-HANA levels in slices from cerebral cortex. No further increases were observed after incubations of up to 120 min. Exposure of cortical slices to 3-HANA's putative bioprecursors, 3-hydroxykynurenine (3-HK) and anthranilic acid (ANA), in the absence of 4-Cl-3-HANA resulted in rapid, transient increases in 3-HANA production. Maximal 3-HANA synthesis from ANA exceeded the maximal effect of 3-HK by approximately 11-fold.2+ In the presence of 4-Cl-3-HANA, 1 mM ANA produced 9.0 +/- 0.3 and 89.0 +/- 9.3 (5 min) or 51.6 +/- 7.9 and 187.5 +/- 11.2 (120 min) fmol of newly synthesized 3-HANA/mg of brain tissue, respectively.(ABSTRACT TRUNCATED AT 250 WORDS)
3-Hydroxyanthranilic Acid↗
Anthranilic acid derivatives: a new class of non-peptide CCK1 receptor antagonists.
Having successfully obtained new CCK(1) ligands holding appropriate groups on the anthranilic acid dimer used as molecular scaffold we were interested in increasing their micromolar affinity for the CCK(1) receptors by modifying the spatial relationship of the main pharmacophoric groups. Since, we have proposed simplified analogues reducing the anthranilic acid dimer to a monomer. In this stage of our research program we have prepared and tested on CCK receptors a series of N-substituted anthranilic acid derivatives keeping a Phe residue at the C-terminal site. The indole-2-carbonyl group imparts the best CCK(1) receptor binding affinity (compound 1: IC(50)=197.5 nM) while a sharp decrease in binding affinity is observed for the other indole containing derivatives. Moreover, in order to support the different binding behaviour observed for the synthesized compounds, a conformational investigation was carried out. Finally, on the basis of the main pharmacophoric groups of the obtained new lead compound (1) (coded VL-0395) a receptor binding hypothesis has been provided.
Animals↗
Synthesis of new anthranilic acid dimer derivatives and their evaluation on CCK receptors.
We have described previously an innovative bond disconnection strategy of asperlicin, a naturally occurring CCK receptor antagonist, leading to anthranilic acid dimer and tryptophan synthons. We have also demonstrated that when the tryptophan residue is connected to the C- or N-terminal sides of the anthranilic acid dimer, compounds with similar micromolar CCK-A receptor affinities are obtained. In order to investigate the binding effects of different N-terminal substitution, in this paper we describe a new series of anthranilic acid dimer derivatives, characterized by the presence of the tryptophan residue in the C-terminus of the dimer. Among the compounds synthesized, the N-1H-indol-3-propionyl derivative exhibited an improved, at the micromolar range, affinity for the CCK-A receptor in comparison to that of either, the N-unsubstituted derivative and asperlicin. The lead compound emerging from this key step of our investigation represents the new starting point for the development of a new class of CCK-A receptor ligands.
Animals↗
Copper(II) interactions with nonsteroidal antiinflammatory agents. II. Anthranilic acid as a potential. OH-inactivating ligand.
It has long been established that copper complexes of inactive substances exert antiinflammatory activity and that copper complexes of nonsteroidal antiinflammatory drugs (NSAIDs) are more active than these drugs by themselves. Based on these observations, it was proposed that copper complexes of NAIDs are their active metabolites. This hypothesis was not confirmed for salicylic acid, however, as computer-aided speciation studies have shown that no copper-salicylate complex can reach significant levels in blood plasma. In view of this result, it was of interest to test with the same technique the influence on copper metabolism of an inactive substance known to be activated by copper. Anthranilic acid was chosen for this test in the present work. First, copper(II)-anthranilate interactions have been investigated by glass electrode potentiometry under physiological conditions. Given the key role of histidine as copper(II) ligand in blood plasma, copper(II)-histidine-anthranilate ternary equilibra have also been determined. Computer simulations of copper distribution have then been run relative to the two main biofluids in respect of global metabolism, i.e., gastrointestinal (g.i.) fluid and blood plasma. Like salicylic acid, anthranilic acid is expected to favor copper g.i. absorption, but cannot either exert any significant influence on plasma copper distribution. Clearly, the fact that anthranilate becomes antiinflammatory when administered with copper cannot originate in any effect of anthranilate on copper global metabolism. Speciation investigations have then been extended to the synovial fluid. Whereas salicylate does not appear to be a better ligand of copper in this medium than in blood plasma at any pH between 7.4 and 5.5, anthranilate on the contrary can mobilize increasing fractions of copper as the pH decreases, i.e., the more inflammation, the more copper is bound to anthranilate. This is in line with the recent observation that salicylate inactivates copper-induced .OH radicals through its bulk scavenging properties whereas .OH inactivation by anthranilate under the same conditions is a direct function of the copper-anthranilate binding. Anthranilate thus seems to correspond to the recently defined notion of .OH-inactivating ligand (OIL). More generally, these results provide a beginning of rationale for the antiinflammatory properties of copper complexes with substances that are active or inactive against inflammation by themselves. The extra antiinflammatory activity induced by copper on NSAIDs appears to be independent of any Cu(II)-NSAID association in vivo. On the contrary, the binding of inactive substances with copper(II) at inflammatory sites seems to be essential to their activation by copper.
Anti-Inflammatory Agents, Non-Steroidal↗
Simultaneous EQCM and diffuse reflectance UV-visible spectroelectrochemical measurements: poly(aniline-co-o-anthranilic acid) growth and property characterization.
Piezoelectric diffuse reflectance spectroelectrochemistry (PDRSEC), a new technique of diffuse reflectance spectroelectrochemistry (DRSEC) in combination with electrochemical quartz crystal microbalance (EQCM), was developed to study the electrochemical copolymerization of aniline and o-anthranilic acid in 1.0 mol l(-1) HClO4 and the properties of these copolymers. The DRSEC using an integral sphere was proven to possess a higher optical sensitivity at the unpolished piezoelectric quartz crystal electrodes used than the mirror reflectance spectroelectrochemistry mode. The copolymers grown from the copolymerization bath of different molar fractions of o-anthranilic acid (F1, relative to the total amount of the two monomers) showed intermediate properties between those of the homopolymers, which varied gradually with F1. The swelling/dissolution behavior of the copolymers vs solution pH was traced via the EQCM frequency and resistance signals, and its large dependence on F1 was found and discussed. In a HAc-NaAc buffer solution at pH 5.6, the amount of adsorbed lysozyme was found to be positively correlated with F1, via an EQCM impedance investigation, demonstrating the feasibility of using poly(aniline-co-o-anthranilic acid) as a load-adjustable immobilization matrix for cationic proteins. The novel PDRSEC method proposed is highly recommended for surface electrochemistry studies at relatively rough electrodes.
Adsorption↗
Role of anthranilic acid in background levels of sulfonamide in porcine livers when determined by the Tishler method.
Anthranilic acid occurs in excised swine livers as a result of temperature abuse before and/or after freezing. The tryptophan metabolite is the major source of the variable non-sulfonamide background level frequently encountered in the Tishler method for determining sulfonamide residues in swine livers. Diazotized anthranilic acid reacts slowly with N-1-(naphthyl)ethylenediamine [k(s-1) = 5.79 (+/- 0.07) X 10(-5)] and the final background level depends on the time elapsed between addition of the coupling agent and spectrophotometric determination. Kynurenine was tentatively identified as a minor source of the non-sulfonamide background level.
Animals↗
Iron requirement of Rhizobium leguminosarum and secretion of anthranilic acid during growth on an iron-deficient medium.
Rhizobium leguminosarum GF160 required iron for growth under aerobic conditions in a chemically defined medium. Maximal growth of bacteria previously depleted in iron was obtained with approximately 50 microM unchelated ferric iron and with glucose as the only carbon source. Growth under iron deficiency did not result in the production of detectable levels of siderophores of either the catechol or hydroxamate types. Growing cells released a Fe3+-reducing agent that was identified as anthranilic acid by paper and thin-layer chromatography, ultraviolet and nuclear magnetic resonance spectroscopy, and mass spectrometry. The amount of anthranilic acid secreted per unit of cell growth was inversely related to the iron concentration in the culture medium and reached concentrations up to 1 mM. Ferric but not ferrous ions were solubilized in the growth medium by anthranilic acid.
Chromatography↗