Theobromine biological activities

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. 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

Three of the most important methylxanthenes are theophylline, theobromine, and caffeine. Methylxanthenes exhibit a similar range of biological activity. 

There are many components in chocolate. The biologically active stimulants are caffeine and theobromine. The amine compounds are tyramine and phenylethylamine or PEA. 

The purine bases, caffeine, theophylline, and theobromine, yield the corresponding 6-monothio- and 2,6-dithio derivatives upon reaction with LR without a solvent under microwave irradiation. Thionation of the carbonyl groups in the nucleobases of nucleotides leads to interesting special types of thiolactams, which are expected to exhibit modified biological activities. P3u imidine nucleosides are selectively thionated in the 4-position of the nu-cleobase. The mild reaction conditions applied allow the conversion of nucleosides with labile glycosidic bonds, such as 5,6-dihydropyrimidine-(113) and 2, 3 -dideoxynucleosides. Thiononucleosides with unnatural bases (114) or sugar moieties (115), (116) can also be prepared. 

Amino[2- C]uracil (301. accessible from ethyl cyanoacetate and [2- C]urea as previously mentioned, is one of the key intermediates in the Traube-type synthesis of labeled uric acid and xanthine, whose methyl homologues are important biologically active natural products. Nitrosation at C5 with nitrous acid and reduction of the nitroso group with sodium dithionate installed the 5-amino group. Heating of the resulting 5,6-[2- C]diaminouracil (441 in formamide or formic acid resulted in the initial formation of the iV-formamide at C5, which cyclized with elimination of water to afford [2- C]xanthine (451 ". (V-methylation with dimethyl sulfate in basic medium under adequate reaction conditions enabled the separate preparation of [2- C]theobromine ... 

These two methylated xanthines are found in quite a number of plants and have been extracted and widely used for centuries. Indeed, they very hkely have been, and remain today, the predominant stimulant consumed by humans. Every time you make a cup of tea or coffee, you perform an aqueous extraction of plant material (tea leaves. Camellia sinenis, 1 %, or coffee beans, Coffea spp., 1-2%) to obtain a dose of 25-100 mg of caffeine. Caffeine is also the active substance (—2%) in mate (used in Paraguay as a tea) made from the leaves of Ilex paraguensis. In coffee and tea, caffeine is the dominant member of the pair, whereas in Theobroma cacao, from which we obtain cocoa, theobromine (1-3%) is the primary source of the biological response. Caffeine acts to stimulate the central nervous system with its main impact on the cerebral cortex, and as it makes one more alert, it is no surprise that it is the chief constituent in No-Doz pills. 

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