Dimethyl-xanthin

A solution of 35.4 g of 1 -bromohexanone-5 in 200 ml of ethanol was gradually mixed at the reflux temperature with vigorous stirring with 39.7 g of theobromine-sodium in 100 ml of water. After 3 hours reflux the unreacted theobromine was filtered off with suction, the fil-trete was evaporated to dryness, the residue was dissolved in water and the solution was extracted with chloroform. The chloroform was distilled off and 1-(5 -oxohexyl)-3,7-dimethyl-xanthine was obtained as residue after recrystellization from isopropanol, it melted at 102°C to 103°C (about 25% yield, calculated on the reacted theobromine). 

HPLC coupled to MS was used for the determination of dimethyl xanthine metabolites in plasma.82 There have also been a number of methods published on the use of HPLC with a PDA detector. In 1996, Mei published a method for the determination of adenosine, inosine, hypoxanthine, xanthine, and uric acid in microdialysis samples using microbore column HPLC with a PDA detector.63 In this method, samples were directly injected onto the HPLC without the need for any additional sample treatment. 

Theophylline (Fig. 20) is structurally very similar to caffeine and present at a low concentration in tea. It is also known as dimethyl xanthine. It is used for the treatments of asthma and COPD, for more than 50 years despite its many side effects. The mechanism of beneficial effect of theophylline is through HD AC activation. 

Precolumn Lichrosorb RP2 10 pm (40x2.1 mm ID), column Ultrasphere ODS 5 pm (250x4.6 mm ID), mobile phase gradient with solvent A 0.01 M sodium acetate and 0.005 M tetrabutylammonium hydrogen sulfate in water (pH 4.9), solvent B same salt concentrations in 50% methanol (pH 4.8). Gradient 0-7.5 min 0 B, 7.5-15 min 0-T5% B, 15-25 min 15-30% B, 25-33 min 30-32% B, 33-38 min 32-45% B and 38-41 min 45-0% 6. Detection UV 280 nm. Peaks 1, xanthine 2, uric acid 3, 3-methyluric acid 4, 7-methyl xanthine 5, 3-methyl xanthine 6, 1-methylxanthine 7, theobromine 8, 3,7-dimethyl uric acid 9, 7-methyluric acid 10, 1-methyluric acid 11, 1,3-dimethyluric acid 12, 1,7-dimethyl xanthine 13, theophylline 14, e-hydroxyethyltheophylline (internal standard) 15, 1,7-dimethyluric acid 16, 1,3,7-trimethyluric acid 17, caffeine, (reproduced with permission from ref. 192, by the courtesy of Journal Chromatographic Science)... 

Other key derivatives, xanthine (2,6-dihydroxypurine, 4) and hypoxanthine (6-hydroxypurine, 5), are formed by the hydrolytic decomposition of nucleic acids. As their systematic names indicate, the well-known CNS stimulants caffeine (1,3,7-trimethylxanthine, 6), theophylline (1,3-dimethylxanthine), and theobromine (3,7-dimethyl-xanthine), found in coffee, tea, and cocoa beans, respectively, are all derived from xanthine. 

Coumarin 7-hydroxylation can be used in vivo with humans as a phenotypic assay. An alternative procedure is to administer caffeine to individuals and determine the conversion of 1,7-dimethyl-xanthine to 1,7-dimethyluric acid, a reaction catalyzed by P450 2A6 (ref [274]). 

Fig. 8.8 Biosynthetic pathway for tropane and purine alkaloids, (a) Tiopane alkaloid ODC ornithine decarboxylase, PMT putrescine Ai-methyltransferase). (b) Purine alkaloid XMT xanthosine W-methyltransferase/7-methylxanthosine synthase, XN 7-methylxanthosine nucleotidase, MXMT 7-methylxanthine Ai-methyltransferase/theobromine synthase, DXMT dimethyl-xanthine Ai-methyltransferase/caffeine synthase) (Adopted from Ref. [15])...

Figure 1 Chemical structures of caffeine and the dimethyl-xanthines. (A) Purine ring nomenclature according to E. Fischer (B) caffeine (C) theobromine (D) theophylline (E) paraxanthine. From Dews (1984).

Caffeine is represented by 1,3,7-trimethylxanthine (Fig. 18.9) and its naturally occurring catabolic products are characterised by demethylation, leading to 1,3-(theophylline), 3,7-(theobromine) and 1,7-dimethyl-xanthine (paraxanthine). The latter is less commonly reported to be a major plant constituent but appears to be the major caffeine metabolite in humans due to N-demethylation catalysed by CYP1A2. However, more than 25 metabolites have been identified and many are pharmacologically active. Theophylline exhibits psychostimulant activities to some extent but is also involved in broncho-dilation and anti-inflammatory activity in the airway. 

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