Uric acid derivatives

In addition to the intramolecular effects, steric factors are of considerable influence. The most usual one consists of steric hindrance to attack on the lactam nitrogen atom. Certain examples of this will be given. By comparison with uracil, it would be expected that uric acid (10) would be iV-methylated in the pyrimidine ring, but that in the imidazole ring 0-methylation should also be possible. However, the experiments of Biltz and Max show that all uric acid derivatives which carry a hydrogen atom in the 9-position are converted by ethereal diazomethane into l,3,7-trimethyl-8-methoxyxanthine (11). The following are examples uric acid and its 1-methyl, 3-methyl, 7-methyl, 1,3-dimethyl, 1,7-dimethyI, 3,7-dimethyl, and 1,3,7-trimethyl derivatives. Uric acid derivatives which arc substituted by alkyl groups in the 3- and 9-positions (e.g., 3,9-dimethyl-, 1,3,9-trimethyl-, and 3,7,9-trimethyl-uric acid)do not react at all with diazomethane, possibly because of insufficient acidity. Uric acids which are alkylated... 

As with adults, the primary organ responsible for drug metabolism in children is the liver. Although the cytochrome P450 system is fully developed at birth, it functions more slowly than in adults. Phase I oxidation reactions and demethylation enzyme systems are significantly reduced at birth. However, the reductive enzyme systems approach adult levels and the methylation pathways are enhanced at birth. This often contributes to the production of different metabolites in newborns from those in adults. For example, newborns metabolize approximately 30% of theophylline to caffeine rather than to uric acid derivatives, as occurs in adults. While most phase I enzymes have reached adult levels by 6 months of age, alcohol dehydrogenase activity appears around 2 months of age and approaches adult levels only by age 5 years. 

The compounds are extensively metabolized, primarily to uric acid derivatives. There is, however, no indication that methylxanthines aggravate gout. 

Disposition in the Body. Rapidly absorbed after oral administration bioavailability almost 100%. Metabolic reactions include V-demethylation and oxidation to uric acid derivatives. About 85% of a dose is excreted in the urine in 48 hours with up to 40% of the dose as 1-methyluric acid, 10 to 15% as 1-methylxanthine and up to 35% as 5-acetylamino-6-formylamino-3-methyluracil and 5-acetylamino-6-amino-3-methyluracil other metabolites excreted in the urine include theophylline, 1,7-dimethylxanthine (paraxanthine), 7-methylxanthine, and 1,3-dimethyluric acid. Less than 10% is excreted in the urine as unchanged drug. The extent of V-acetylation is genetically determined. Caffeine, theophylline, theobromine, and paraxanthine are found in plasma from dietary sources especially coffee, tea and cocoa. An average cup of coffee or tea contains approximately 100 mg of caffeine. 

The increase in protonation sites in the oxopurines with increasing oxygen functions extends the possibilities for Ai"-alkylation sites. Normally in the case of monooxo- and dioxo-purines, with the exception of reactions with diazoalkanes, many of which are probably free radical in nature, alkylating agents even in alkaline solutions produce only Af-alkyl derivatives. Trioxopurines such as uric acid derivatives are an exception. The nature of the alkylation and the site(s) of attack nevertheless still vary according to the solvent, pH and temperature. 

A 2- or 6-hydroxy-substituted purine can be prepared from the corresponding 4,5-diamino-pyrimidinol by cyclization with an acid, ester, ortho ester, or amide. If the ring closure is performed with reagents such as urea, alkyl chloroformates, urethanes, phosgene, and alkyl isocyanates, the 8-hydroxypurines are formed. Various xanthine and uric acid derivatives have been prepared by the condensation of 5,6-diaminopyrimidine-2,4-diols with formic acid. Purin-2-ol (1) was prepared by this route from 4,5-diaminopyrimidin-2-ol and ethyl orthoformate. ... 

The highest susceptibility to oxidation with chlorine is found in trioxopurines therefore, the major studies have been carried out with uric acid derivatives. Some contributions from xanthine chemistry have also been made. Chlorination of theobromine (1) in aqueous solution gives 4,5-dihydroxy-3,7-dimethyl-4,5-dihydrouric acid (2) while chlorination in dilute acetic acid affords 5-chloro-3,7-dimethylisouric acid (3). ° " ... 

Oxidation of xanthine or uric acid derivatives with chromic acid gives the appropriate alloxane and urea as primary products which undergo further oxidation to corresponding parabanic acids (imidazolidine-2,4,5-triones) and purpuric acids which, on addition of ammonia, constitute the murexide test. This is positive for all purines capable of oxidation to an alloxane derivative, For a review see ref 48. 

Allopurinol is a uricosuric drug used in chronic gout that prevents formation of uric acid from purines by acting as a suicide substrate of xanthine oxidase. The drug is commonly used in patients undergoing treatment of cancer to slow down formation of uric acid derived from purines released by the cytotoxic action of drugs or radiation. The metabolism of 6-mercaptopurine (6-MP), a substrate for xanthine oxidase, is also inhibited by allopurinol, necessitating a major dose reduction to avoid its toxic effects. 

International Critical Tables, Vol. 6, McGraw-Hill, NY, 259-304 (1929). NB From Wood JK, The acidic constants of some ureides and uric acid derivatives, /. Chem. Soc, 89,1831-1839 (1906). Of historical interest only. 

Uric acid that is produced in man is essentially the product of the action of the enzyme xanthine oxidase on xanthine and hypoxanthine. A tiny amount of uric acid may be ingested as part of the diet, but the great bulk is the result of the action of this enzyme on these two purines. These purines are themselves produced either as a result of the breakdown of cellular material in toto, the turnover of nucleic acids in the cells, or as a result of the intermediary metabolism of various purine nucleotide derivatives. These latter compounds are active in the flow of energy, in methyl group transfer reactions, and as part of the functional molecule of many vitamins. There is direct and indirect evidence that some of the uric acid derives from all these sources. Essentially this evidence consists of the demonstration that other parts of the nucleie acids are found in the urine, such as pyrimidine breakdown products (P9) and methylated purines, which are found only in nucleic acids. There is also isotopic evidence that some labeled purines appear in the urine too quickly after administration of radioactive precursors... 

The product of nucleophilic attack of water on the diimine primary product of electrochemical oxidation of uric acids is an imine-alcohol (see Figure 25). This species is characterized in the case of uric acid in terms of its reduction peak lie observed under cyclic voltammetric conditions and its uv absorption spectrum under thin-layer spectroelectrochemical conditions. Reduction peak lie niay be observed on cyclic voltammetry of all uric acid derivatives. The general reaction involved in forming the imine-alcohol intermediate from neutral or anionic diimines in the case of the group I uric acids is shown in Figure 25. In the case of the positively charged diimines formed upon oxidation of the group II uric acids, the reaction scheme is illustrated in Eq. (17). That... 

Observed First-order Rate Constants for Reaction of the UV-Absorbing Intermediate Formed on Enzymic (Peroxidase) and Electrochemical Oxidation of Uric Acid Derivatives at pH 7 ... 

Such results reveal that upon electrochemical and enzymic (peroxidase) oxidation of uric acid and uric acid derivatives a uv-absorbing intermediate is formed. The spectral, kinetic, and electrochemical behavior of this intermediate whether generated enzymically or electrochemically are identical. Analytical data on the trapped and derivatized electrochemical intermediate are in accord with the uv-absorbing intermediate having an imine-alochol structure (i.e.. Ill, Figure 25). 

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