Hydroxyanthranilic acid derivatives

Linderberg M, Hellberg S, Bjork S, Gotthammer B, Hogberg T, Persson K, Schwarcz R, Luthman J, Jo-hansson R (1999) Synthesis and QSAR of substituted 3-hydroxyanthranilic acid derivatives as inhibitors of 3-hydroxyanthranilic acid dioxygenase (3-HAO). Eur J Med Chem 34 729-744... 

Alkaloids derived from nicotinic acid contain a pyridine nucleus. Nicotinic acid itself is synthesized from L-tryptophan via A-formylkynurenine, L-kynurenine, 3-hydroxykynurenine, 3-hydroxyanthranilic acid and quinolinic acid. 

It was furthermore reported (K20) that nicotinic acid-deficient animals would grow only if given tryptophan, thus suggesting the conversion of tryptophan to nicotinic acid. Not only is tryptophan converted to nicotinic acid but also kynurenine and 3-hydroxyanthranilic acid. The peculiar degradation of the latter to pyridine derivatives gave rise to many interesting investigations. 3-Hydroxyanthranilic acid is derived from 3-hydroxykynurenine, another important tryptophan metabolite, the his-... 

The pieces of paper with 3-hydroxykynurenine, 3-hydroxyanthranilic acid, and xanthurenic acid are each placed in an Erlenmeyer flask fitted with a ground-glass stopper and containing 3.8 ml distilled water. After 15-16 hours, 1 ml diazotized sulfanilic acid (0.5% in 2% hydrochloric acid mixed immediately before using with an equal volume of 0.5% solution of sodium nitrite in water) and 0.2 ml pyridine are added. The temperature must be held constant at 15° to obtain reproducible results. The color resulting from xanthurenic acid is read immediately at 510 mp, and of the other two derivatives after 60-80 minutes at 450 mp. 

From our investigation it is evident that abnormal excretion of tryptophan metabolites is not a typical feature of bladder tumor subjects, since human beings with neoplastic and nonneoplastic extrabladder urinary diseases have also been found to excrete spontaneously elevated amounts of tryptophan derivatives. It seems that the metabolic abnormality is not restricted to bladder tumors, but is rather more specific for patients with tumors of the upper urinary tracts and of the renal parenchyma. Actually 59% of these patients (Fig. 4) excreted abnormal amounts of kynurenine, 3-hydroxykynurenine, and 3-hydroxyanthranilic acid. 

It is generally accepted that under normal conditions human subjects convert the largest part of an ingested dose of L-tryptophan to non-aromatic products. The last identified benzene derivative on this pathway is 3-hydroxyanthranilic acid when its ring is opened to form unstable intermediates, apparently only a small percentage of them are converted to niacin (H8). 

These patients appear to excrete a slightly higher amount (8.9-12.3%) of tryptophan derivatives than normals (average 6.7%), The excretion ratios are different for each metabolite the highest ratio is found for 3-hydroxykynurenine and the lowest for 3-hydroxyanthranilic acid. 

Isotopic experiments (763) with tryptophan labeled with N and deuterium in the indole ring have shown that quinolinic acid nitrogen is probably entirely derived from the indole nitrogen of tryptophan, and that scission of the benzene ring probably occurs between carbons 3 and 4. Presumably, therefore, the hydroxyanthranilic acid is converted to intermediate A without participation of a catechol-type intermediate, and it is possible that the phosphate-bond energy of hydroxyanthranilic acid phosphate (if this is in fact an intermediate) may contribute to the transformation. It is known... 

It is remarkable that the intermediates in the conversion of hydroxyanthranilic acid to nicotinic acid are still not known with certainty. Intermediates A and B of diagram 21 are plausible suggestions, but no synthesis of either has been reported. Both are extremely unlikely to be stable in the free state, but should be obtainable as simple derivatives. In the free state Intermediate A, for example, might be expected to tautomerize to the imino acid, and hence give keto acid and ammonia, or it could cyclize to a piperazine or to quinolinic acid. Tautomerism through the imino acid would eliminate the necessity for a fumaric —> maleic isomerization. It is quite possible that spontaneous cyclization explains the prominent part quinolinic acid plays in work on hydroxyanthranilic-nicotinic conversion. If the latter occurred in the following.way ... 

The relation of many of the simpler alkaloids to the aromatic amino acids is obvious. For example, germinating barley contains (241), besides tyrosine and tyramine, A -methyltyramine, JViV -dimethyltyramine (hordenine), and the trimethylammonium derivative (candicine). In this simple case the. AT-methylated derivatives are known to be derivable from isotopically labeled tyramine (538) and the methyl groups are known to arise from methionine by transmethylation (540, 586). Similarly AT-methyl derivatives of phenylethylamine, 3,4-dihydroxyphenylethylamine, and 3,4,5-trihy-droxyphenylethylamine are well known alkaloids (cf. review, 701). N-Methylated derivatives of tryptamine and hydroxytryptamine equally occur for example, eserine has an obvious relation to 5-hydroxy tryptamine. Methylated derivatives of metabolites of the aromatic amino acids also occur, for example, trigonelline (67), which is the betaine of nicotinic acid, and damascenine is probably similarly related to hydroxyanthranilic acid. 

Kynureninase catalyzes the hydrolytic cleavage of both kynurenine and 3-hydro-xykynurenine to generate anthranilic acid and 3-hydroxyanthranilic acid, respectively [55]. The majority of inhibitors of kynureninase are substrate based and are designed based on the postulated transition state intermediate where water attacks the benzoyl group carbonyl through a PLP-dependant mechanism. The hydroxy (16 = 0.3 pM) and sulfone (17 IC50 =11 pM) derivatives have... 

In several instances polymeric substances arise during the transformation of secondary products, such as polymeric carbohydrates (D 1.4.1), humic acid-like polyphenols (D 3.3.1), rubber (D 6), sporopoUenins (D 6.5), polymeric products derived from 3-hydroxyanthranilic acid (D 8.4.1), melanins (D 22.1.3), lignins (D 22.2.3), and muramin (D 23.4). Many of these compounds are formed by oxidative polymerization catalyzed by phenoloxidases (C 2.3.1) and peroxidase... 

Dehydroquinic acid, shikimic acid, and chorismic acid are carboxylated compounds containing a six-membered carbocyclic ring with one or two double bonds (Fig. 143). The secondary products derived from these substances either still contain the ring and the C -side chain of the acids (see the structure of the benzoic acid derivatives, of anthranilic and 3-hydroxyanthranilic esters, D 8, D 8.2, D 8.4 and D 8.4.1) or have additional rings (see the formulae of naphthoquinones and anthraquinones, D 8.1, of quinoline, acridine, and benzodiazepine alkaloids, D 8.3.2). The carbon skeletons may be substituted by isoprenoid side chains (see the structure of ubiquinones, D 8.3) and may carry different functional groups, e.g., hydroxy, carboxy, methoxy, and amino groups. 

The secondary products derived from anthranilic acid (o-amino benzoic acid) may carry additional substituents at the aromatic ring, e.g., hydroxy groups (see formula for hydroxyanthranilic acid) or at the carboxyl and the amino group. The latter substituents may form additional rings. 

Hydroxyanthranilic acid and its derivatives are formed in microorganisms, plants and animals. 

Nicotinic Add Metabolism. The sequence of reactions leading to the formation of pyridine compounds is of particular interest as a source of nicotinic acid. Nutritional, isotopic, and genetic experiments have all shown that tryptophan and its metabolic derivatives including 3-hydroxy-anthranilic acid are precursors of nicotinic acid in animals and in Neuro-spora. The terminal steps in this sequence are not known. Under certain physiological conditions an increase in picolinic carboxylase appears to reduce nicotinic acid synthesis. This implies a common pathway as far as the oxidation of 3-hydroxyanthranilic acid. Whether quinolinic acid is a precursor of nicotinic acid is still uncertain. The enzyme that forms the amide of nicotinic acid also has not been isolated. Subsequent reactions of nicotinamide include the formation of the riboside with nucleoside phosphorylase and methylation by nicotinamide methyl-kinase. In animals W-methylnicotinamide is oxidized to the corresponding 6-pyridone by a liver flavoprotein. Nicotinic acid also forms glycine and ornithine conjugates. Both aerobic and anaerobic bacteria have been found to oxidize nicotinic acid in the 6-position. ... 

This enzyme has been shown to occur in liver and kidney and also in certain microorganisms. It decomposes L-kynurenine to anthranilic acid and hydroxykynurenine to 3-hydroxyanthranilic acid. According to Wiss and Fuchs, the enzyme is able to split a variety of compounds containing the —COCH2CH(NH2)COOH group. Braunstein et observed that alanine was produced by the fission of the side chain and that a pyroxidine derivative was the coenzyme for the reaction. 

Other tracer experiments with N Mabeled 3-hydroxyanthranilic acid have shown that niacin and quinolinic acid are both derived quantitatively from this compound." The evidence which has been given above is in good agreement with the scheme for the formation of nicotinic acid given in Fig. 8. 

A group of about 40 amides derived from 5-hydroxyanthranilic or 5-hydroxy-4-methoxyanhranilic acids and cinnamic acids, trivially named avenanthramides, are important phytoalexins unique to oat grains Avena sativa, Poaceae). The dominant compounds are derivatives of 5-hydroxyanthranilic acid avenanthramide Bp derived from p-coumaric acid (also called avenanthramide A, 8-154), avenanthramide Be derived from caffeic acid (also called avenanthramide C) and avenanthramide Bf derived from ferulic acid (also called avenanthramide B). The main compound (40-132 mg/kg) is avenanthramide Bf (8-154). Approximately 6% of oat antioxidants are anthramides derived from caffeic acid. 

These studies were confirmed by tracer experiments showing that nitrogen of nicotinic acid (formed by Neurospora) is derived from 3-hydroxyanthranilic acid (478). Experiments with doubly labeled tryptophan demonstrate that tryptophan is probably the only source of quinolinic acid in rat metabolism (645) and that carbon atom 3 of tryptophan, the precursor of the carboxyl carbon of 3-hydroxyanthranilic acid, becomes carboxyl carbon in nicotinic acid (310,340,341,373). In vitro studies of the enzymic oxidation of 3-hydroxyanthranilic acid confirm its relationship to quinolinic acid (498) and show that picolinic acid may also form from it (539,540) but nicotinic acid synthesis under... 

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