Methylxanthine alkaloids

The major analytes of coffee include caffeine, chlorogenic acids, and flavor and volatile aromatic components. The major analytes in cocoa are me-thylxanthines, mainly theobromine and trace amounts of caffeine, cocoa fat, and lipids. Other analytes of interest in cocoa are tannins, pigments, and aroma components. The major analytes of tea are the methylxanthine alkaloids, including caffeine and theophylline, polyphenols (catechins, tannins, and related flavanols), and volatile and aromatic components. Analysis of black tea would also include theaflavins and thearubigens, which are oxidation and condensation products of polyphenols. 

Pentoxifylline is stmcturaHy related to other methylxanthine derivatives such as caffeine [58-02-2] (1,3,7-trimethylxanthine), theobromine [83-67-0] (3,7-dimethylxanthine), and theophylline [58-55-9] (3,7-dihydro-1,3-dimethyl-1 H-piirine-2,6-dione or 1,3-dimethylxanthine), which also show radioprotective activity in some instances, suggesting that methylxanthines as a dmg class may radioprotect through a common mechanism (see Alkaloids). In a retrospective analysis of cervical and endometrial cancer patients receiving primary or adjuvant XRT, no association between caffeine consumption and incidence of acute radiation effects has been found. However, there was a decreased incidence of severe late radiation injury in cervical cancer patients who consumed higher levels of caffeine at the time of thek XRT (121). The observed lack of correlation between caffeine consumption and acute radiation effects is consistent with laboratory investigations using pentoxifylline. 

Purine is the parent heterocyclic compound of the methylxanthines, which are often referred to as the purine alkaloids.1-7 Purine is also the parent compound of some of the base constituents of the nucleotides, which in turn are part of the nucleic acids RNA and DNA. Thus, it appears that the purine alkaloids have similar precursors to nucleic acids. 

The analysis of the methylxanthines (caffeine, theobromine, and theophylline) is important in the areas of nutrition and clinical chemistry. These three compounds compose the majority of the alkaloids present in coffee, tea, cocoa, cola nuts, and guarana. 

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. 

Although low levels of methylxanthines have been detected in the leaves and flowers of T. cacao, the primary storage location is within the seed or bean.16 The cocoa bean is the major natural source of the methylxanthine theobromine, but contains only small amounts of caffeine. Theophylline has been detected in cacao beans, but at such low concentrations that its presence generally is ignored. Together, theobromine and caffeine account for up to 99% of the alkaloid content of T. cacao beans. Alkaloid content is affected by genetic makeup, maturity of beans at harvest, and fermentation process. Analytical methodology also is partially responsible for some of the disparity in methylxanthine values since many early methods were unable to separate theobromine and caffeine. 

A plant-derived compound used in the treatment of asthma and COPD is the methylxanthine-type alkaloid, theophylline (50), found naturally in tea Camellia sinensis Kuntze). This compound demonstrated higher activity when complexed with bases, as in its semisynthetic analogue amino-phylline (51). 5... 

A cnp of coffee can contain 50-150 mg of caffeine, and cola drinks can have 35-55 mg. Theophiline,l,3-dimethylxanthine, a principal, characteristic alkaloid of tea, and theobromine, 3,7-dimethylxanthine (23.3.19), a principal alkaloid of cocoa, are among a number of methylxanthines. In small doses, caffeine is a relatively weak psychostimulant and is used for increasing awareness as well as for relieving headaches associated with blood flow disorders of the brain. Caffeine has a stimulatory effect on the respiratory and vasomotor centers, and it stimnlates centers of the vagus nerve. It has a direct stimulatory effect on the myocardium, and in large doses can cause tachycardia and arrhythmia. 

As a category of alkaloids with distinctive bioactivity, methylxanthine derivatives have in recent years received increasing attention in the food and pharmaceutical industries. The most important compounds of this class, characterized by a bitter flavor, are caffeine CF, theobromine TB, and theophylline TP (Fig. 6). 

Caffeine (Fig. 11.3), widely used by humans as a stimulatory drug, has so far been detected only in a few plant species. The biological roles of caffeine are believed to be in defense against herbivory or as an allelopathic response to potential competitors.83 Caffeine is derived from the purine alkaloid xanthosine. From xanthosine, three methylations are necessary to produce caffeine. First, xanthosine is methylated on N7 by 7-methylxanthosine synthase (MXS or 7NMT) to produce 7-methylxanthosine, which is enzymatically hydrolyzed to produce 7-methylxanthine and ribose.85,86 The methylations of N1 and N3 of 7-methylxanthine to produce 1,3,7-trimethylxanthine (caffeine) occur in young leaves of tea, and the same enzyme, caffeine synthase, apparently catalyzes both reactions.55 In coffee plants, caffeine is mainly found in the beans but also occurs in the leaves. Caffeine is stored in the vacuoles of coffee leaves as a complex with polyphenols such as chlorogenic acid.87 In contrast to tea, coffee plants appear to have separate enzymes for each step of N-methylation.57... 

The alkaloids are basic compounds in which an N atom is typically part of a heterocyclic ring but in some cases is merely a substituent of an alicyclic or aromatic ring system (as for example with colchicine, some peptide alkaloids and some Amaryllidaceae alkaloids). Various N-based heterocyclics such as the purine and pyrimidine bases of DNA and RNA (see Chapter 2) and the methylxanthine purine derivatives variously found in tea and coffee (caffeine, theobromine and theophylline) are sometimes referred to as pseudoalkaloids and for consistency will be included as alkaloids in this classification. Indeed all plant heterocyclics with a ring N will be conveniendy lumped in with the alkaloids in the tables for didactic simplicity and consistency. 

While skeletal muscle ryanodine receptors are involved in excitation — contraction coupling through direct interactions with voltage-gated Ca2+ channels, in other cell types ryanodine receptor Ca2+ channels located on the ER membrane are opened by cADPR in a Ca2+-CaM-dependent fashion. Ca2+ and plant metabolites such as the diterpenoid alkaloid ryanodine and the methylxanthine caffeine promote opening of the ryanodine receptor Ca2+ channel. Ryanodine can also negatively modulate the receptor (Table 4.4). 

Caffeine (= 1,3,7-Trimethylxanthine Coffeine Guaranine Thein Theine) (purine, methylxanthine) most consumed plant bioactive alkaloid Over 4 million tons of coffee produced each year... 

The prototypical structural class of nonselective PDE inhibitors is represented by the methylxanthines (Figure 9.4), a family of plant-derived alkaloids that includes theophylline (1), caffeine (2), and theobromine (3) [9], Although limited in potency, these simple naturally occurring xanthines were the parents in the later discoveries of more potent synthetic derivatives such as pentoxyfylline (4) and isobutylmethyl-xanthine (IBMX, 5). In particular, the latter compound has been widely used and has been regarded for decades as the gold standard nonselective inhibitor of all PDEs. Only recently has it become clear that some of the newer PDEs (8 and 9) are not inhibited by IBMX. Derivatives of IBMX carrying substituents at the 8 position confer increased potency [10], An example is compound 6, which retains most of... 

Caffeine is an alkaloid classified as a methylxanthine, a group of closely related compounds including caffeine, theophylline, and theobromine, that have similar physiological effects. Caffeine is the most widely consumed... 

C7H8N4O2, Mr 180.17, thin, bitter-tasting platelets, mp. 270-274 °C (monohydrate), moderately soluble in water, very soluble in hot water, alkali hydroxides, ammonia, dilute acids. A purine alkaloid from the leaves of the tea plant, also contained in matd (Ilex paragua-riensis and Paullinia cupana). The methylxanthines T., caffein(e), and theobromine are among the oldest known stimulants and drugs. Their pharmacological properties are compared in the table. In high doses T. can cause epilepsy-like convulsions. T. also exhibits antiasthmatic activity. ... 

Figure 6.59 Structure of purine alkaloids methylxantines (7-methylxanthine, theobromine, caffeine, theophylline, and paraxanthine) and methyluiic adds (theacrine, 1,3,7-lrimethyluric acid, methylliberine, and liberine).

Both purine and pyrimidine bases occur as constituent parts of nucleic acids and plant products. In addition, a number of free purine and pyrimidine bases have been isolated from plants (Atta-ur-Rahman and Choudhary, 1990 Brown, 1991 Wang, 1973). The pyrimidine glucoside vicine (28) was first isolated from seeds of Vida species in 1870. However, purine bases appear to be much more common that pyrimidine bases in nature. The most important purine alkaloids are derived from the xanthine nucleus. Xanthine itself has not been found naturally, but several of its A -alkyl derivatives are of considerable importance. The most important of these are 1,3,7-trimethylxanthine (caffeine) (29), 1,3-di-methylxanthine (theophylline) (30), and 3,7-dimethylxan-thine (theobromine) (31) (Fig. 37.9). These alkaloids are major constituents of plants used as stimulating beverages by people throughout the world. 

Camellia (Thea) sinensis (tea) and Cqffea arabica (coffee) plants. Caffeine was formed rapidly by extracts of green coffee berries, but little by more mature ones, and not at all by seedlings. Biosynthesis of caffein proceeds from 7-methylxanthosine in the presence of an active purine nucleoside phosphorylase or 7-methyl-A -nucleoside hydrolase. Methionine and 5-adenosylmethionine serve as precursors for the methyl groups of purine alkaloids. These act in the presence of methyltransferases on 7-methylxanthine (38) and theobromine (31) to produce caffeine. A pathway for the origin of these compounds in coffee and tea plants has been proposed (Suzuki et al., 1992 Waller and Dermer, 1981) (Fig. 37.10). 

In recent years, the studies of cocoa and cocoa products (cocoa powder, dark chocolate, and cocoa liquor) and their related products have become an area of interest given their health-promoting properties due to the presence of bioactive compounds such as the flavanols (catechins and proanthocyanins), the flavonoids subgroup, and alkaloids (methylxanthines). Several in vitro and in vivo studies have suggested that polyphenols may protect against many degenerative diseases. A relation has been found in some of these between the consumption of cocoa derivatives and their cardiovascular effect [1,2],... 

These three alkaloids are well-known compounds, as they are present in everyday foods and beverages, such as cocoa, drinking chocolate, tea, and cola, as well as in pharmaceutical products. In cocoa products, theobromine is the major alkaloid, followed by caffeine, which is found in small quantities. Slight traces of theophylline have been identified therefore, it is not considered relevant and is not reviewed in the cocoa products [22,23], The range of methylxanthines also depends on variables such as the origin of the cocoa beans, the fermentation process, and the cocoa production process. Thus, for instance, defatted cocoa beans may contain about 4% and 0.2% of theobromine and caffeine, respectively [24], Regarding their physiological effects in humans, methylxanthines have been related to various body systems, mainly the central nervous system, but also the cardiovascular, renal, and respiratory systems [25,26],... 

With regard to alkaloids analysis, theobromine was the main compound found in cocoa extracts. This is in agreement with this compound being the most important methylxanthine found in products from the cocoa tree, Theobroma cocao [22], Theobromine was also detected at higher concentrations than caffeine. These were around 42 and 3.5 mg/g lyophilized cocoa extracts (beans, nibs, liquor, and powder) [28],... 

Alkaloidal amines are methylated xanthines forming weak bases that are pharmacologically active. There are three methylxanthines and all are present in our most popular stimulant beverages—coffee and tea. 

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])...

In a narrow sense, purine alkaloids comprise methylxanthines and methyluric acids [1]. This chapter, however, also includes information on cytokinins, which are purine ring-containing phytohormones, and the purine-like neurotoxin alkaloids, saxitoxin and tetrodotoxin. 

---