Methylated xanthines

Ndjouenkeu, R., Clo, G., Voilley, A., Effect of coffee beverage extraction conditions on the concentration in methyl xanthines measured by HPLC, Scl. Aliments., 1, 365, 1981. (CA95 202163c)... 

Foods derived from cocoa beans have been consumed by humans since at least 460 to 480 AD. The source of cocoa beans, the species Theobroma, contains a variety of biologically active components. These include the purine alkaloids theobromine, caffeine, and theophylline. Structurally, they are methylated xanthines and, thus, are often referred to as methylxanthines. Theobromine (3, 7-dimethylxanthine) is the predominant purine alkaloid in cocoa and chocolate. Caffeine (1, 3, 7-trimethylxanthine), the major purine alkaloid found in coffee and tea, is found in cocoa and chocolate at about one eighth the concentration of theobromine. Only trace amounts of theophylline (1, 3-dimethylxanthine) are detected in cocoa and chocolate products. 

In the case of the methylated xanthines, particularly theophylline, theobromine and caffeine, the preponderance of data on the metabolism of these compounds in man suggests that a methylated uric acid is the principal product. However, the data presented earlier proposes at best a 77 per cent accounting of the methylated xanthine administered. The question can be raised as to whether the final products observed upon electrochemical oxidation of these compounds aids these studies. Very recently studies of metabolism of caffeine have revealed that 3,6,8-trimethylallantoin is a metabolite of caffeine 48>. This methylated allantoin is, of course, a major product observed electrochemically. The mechanism developed for the electrochemical oxidation seems to nicely rationalize the observed products and electrochemical behavior. The mechanism of biological oxidation could well be very similar, although insufficient work has yet been performed to come to any definite conclusions. There is however, one major difference between the electrochemical and biological reactions which is concerned with the fact that in the former situation no demethylation occurs whereas in the latter systems considerable demethylation appears to take place. 

In attempts to prepare methylated xanthine analogues with greater therapeutic effectiveness as diuretic and cardiac drugs than theophylline (LXIV) and theobromine (LXV), it was found that some of the intermediate 6-aminouracils (LXVI) showed considerable activity as oral diuretics in experimental animals... 

Figure 1. Some Naturally Occurring Methylated Xanthines.

Furukawa, C. T. (1988). Comparative trials including a beta 2 adrenergic agonist, a methyl-xanthine, and a mast cell stabilizer. Ann. Allergy 60,472-476. 

The HPLC-FTIR technique has recently been used to identify six catechins and two methyl-xanthines present in green tea extracts." " A reversed-phase separation of the compounds was performed on a C-18 column equilibrated at 30°C using an isocratic mobile phase of acetonitrile-0.1% formic acid (15 85), prior to introduction to the deposition interface linked to the FTIR detector. The solvent was evaporated at 130°C and spectra were collected every 6 sec during the run. Two distinct designs for HPLC-FTIR interfaces have been developed flow cells and solvent elimination systems. Flow cell systems acquired spectra of the eluent in the solvent matrix through IR transparent, nonhydroscopic windows. The... 

Der Austausch von Kohlenstoff-Resten am Ring-C-Atom von Imidazolen ist eine nur sehr selten verwendete Reaktion. Gebrauchlich ist hier lediglich der Abbau von Carbonsaure-N-Derivaten nach Curtius, Schmidt oder Lossen. So gelingt z.B. aus 4,5-Bis-[aminocarbonyl]-l-methyl-imidazol mit Natriumhypobromit in 60% Ausbeute die Herstellung von 9-Methyl-xanthin"7. 

Theoretical explanations for the stimulatory activity of the methyl xanthines ... 

Effects relaxation of bronchi, increase in respiration, stimulation of cardiac muscle, diures(f> Methyl xanthines are used in the treatment of asthma. 

The second messenger system can be affected by a number of xenbiotics both simple molecules and bacterial toxins. See the ASIDES which discuss the effects of methyl xanthines such as caffeine as well as the effects of cholera and pertussis (whooping cough) toxins on cyclic AMP. 

Theoretical explanations for the stimulatory activity of the methyl xanthines. These compounds inhibit phosphodiesterase reaulting in the prolonged activ of metabolic enzymes.Adenylate cyclase activity is modulated by the bindin free adenosine. The methyl xanthines are antagonists to adenosine but the bindings do not produce its modulating (inhibitory, attenuating) response. Therefore the end result is stimulatory in relation to cAMP activity. 

The intracellular signal therefore persists only as long as the hormone receptor remains occupied by epinephrine. Methyl xanthines such as caffeine and theophylline (a component of tea) inhibit the phosphodiesterase, increasing the half-life of cAMP and thereby potentiating agents that act by stimulating adenylyl cyclase. 

ATP, ADP, and adenosine are among the purines that are present in some synapses and activate a variety of receptors. Adenosine receptors are blocked specifically by methylated xanthines such as caffeine (Fig. 25-18) and theophylline.808 80813 A drug almost 105 times as potent as theophylline is l,3-dipropyl-8-(2-amino-4-chlorophenyl)xanthine.809 Adenosine receptors, which are present in large numbers in the hippocampus,149 form functional complexes with metabotropic glutamate receptors.678 Adenosine... 

Methybanthine Diuretics. The meihytxanihine.s are of very limited efficacy when used as diuretics. The excretion of sodium and chloride ions are increased, but the potassium excretion is normal. Even though the methyl xanthines have been demonstrated to have minor direct effects in the renal tubules, it is believed that they exert (heir diuretic effects through increased renal blood flow and GFR. 

Caffeine, the active substance responsible for the stimulant effect of the coffee plant s berry, is a methyl-xanthine, one of the family of stimulants present in more than 60 species of plants. The pure chemical forms white, bitter-tasting crystals, which were first isolated from coffee in 1820. Other family members are theophylline, found in tea leaves, and theobromine, found in the cacao pods that are ground to make chocolate. The most potent component in the coffee family by unit weight is theophylline, while theobromine, the weakest component by unit weight, stays in the body longer than does caffeine. 

Antioxidant activities of caffeine (1,3,7-trimethylxanthine) and its main metabolites was compared. Caffeine, 1,7-dimethylxanthine, and 3,7-dimethylxanthine did not show any peroxyl radical-scavenging capacity at concentration up to 100 fxM. Flowever, the relative antioxidant activities (with respect to Trolox) of 1-methyl-xanthine and 1-methyluric acid were 0.82 and 0.58, respectively (L9). 

The heteroaromatic betaines, [l,3,4]thiadiazolo[3,2-a]pyrimidine-5,7-diones (753), which are isoconjugate with methylated xanthines, are in the same way as the latter found to be inhibitors of cyclic AMP phosphodiesterase (78JPS1762). The N-/3-D-ribofuranosyl nucleoside (754) inhibits the synthesis of RNA and DNA but not of protein. The primary blockade is in the synthesis of purine nucleotides (79MI42902). RNA synthesis is also inhibited by [l,3,4]thiadiazolo[3,2-a]pyrimidines of structure (755). The activity is attributed to the chemical reactivity at C-2 leading to reactions with an SH or OH group in RNA polymerase (80ABC1923). Compounds with the 7-oxo formula (756) are claimed to be useful as immune enhancers (78GEP2712932). 

FIGURE 7-5. A 0 to 10% gradient separation of polar compounds. Components (1.0 p.g each) (1) uracil, (2) hypoxanthine, (3) 3-methyl xanthine, (4) theobromine, (5) theophylline, and (6) /3-hydroxyethyl theophylline. Solvent A 0.01 M sodium ace-tate/water. Solvent B acetonitrile. Flow rate 2.0 mL/min. Gradient 0-10% solvent B using a linear shape (top line). Run time 50 min. Injection volume 15 p.L. Column Radial-Pak Resolve Cig (10 /xm) 8 mm ID x 10 cm. Detector UV at 254 nm, 0.1 AUFS. (Reproduced from reference 1 with permission.)... 

No doubt the commercial importance of the various methylated xanthines such as theobromine, theophylline and caffeine has contributed to the substantial literature on... 

Methylxanthine is the major purine constituent of human urine (3.1 g in 10001) (1898ZPC(24)364). 3- and 7-Methylpurines are also minor constituents of urine, especially following large doses of caffeine or other methylated xanthines. 1,3-Dimethylxanthine (theophylline) occurs with caffeine in tea leaves and is a powerful diuretic and has been used clinically for this purpose (generally as an adduct with salts of organic acids) and also in the treatment of asthma. 1,7-Dimethylxanthine (paraxanthine) is also an efficient diuretic and, in addition, possesses antithyroid properties (45JCS751). The main purine constituent... 

Ogawa M, Herat Y, Koizumi N, Kusano T, Sano H. 7-methyl-xanthine methyltransferase of coffee plants. Gene isolation and enzymahc properties. J. Biol. Chem. 2001 276 8213-8218. 

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