Xanthines naturally-occurring

For many years oral xanthines, shown in Table 2, were the preferred first-line treatment for asthma in the United States, and if the aerosol and oral formulations of P2" go sts are considered separately, as they are in Table 1, this was still the case in 1989. Within this class of compounds theophylline (8), or one of its various salt forms, such as aminophylline [317-34-0] (theophylline ethylenediamine 2 l), have been the predominant agents. Theophylline, 1,3-dimethylxanthine [58-55-9], is but one member of a class of naturally occurring alkaloids. Two more common alkaloids are theobromine (9), isomeric with theophylline and the principal alkaloid in cacao beans, and caffeine, (10), 1,3,7-Trimethylxanthine [58-08-2], found in coffee and tea. 

Adenine (6-amino purine) and guanine (2-amino-6-oxy purine), the two common purines, are found in both DNA and RNA (Figure 11.4). Other naturally occurring purine derivatives include hypoxanthlne, xanthine, and uric acid (Figure 11.5). Flypoxanthine and xanthine are found only rarely as constituents of nucleic acids. Uric acid, the most oxidized state for a purine derivative, is never found in nucleic acids. 

FIGURE 11.5 Other naturally occurring purine derivatives—hypoxanthine, xanthine, and uric acid. 

Figure 1. Some Naturally Occurring Methylated Xanthines.

G. Dryhurst and co-workers have investigated the electrochemistry of naturally occurring JV-heterocyclic molecules, including uric acid, xanthine, adenine, and guanine,5,402 in the expectation that the mechanisms observed electrochemically might lead to a more detailed understanding of the biological redox reactions of these molecules. 

Materials and processing technologies. The polymers discussed previously for nonenteric coatings such as HPMC (the most widely used), PVP, CMC, and carbomer, xanthin gum, and other naturally occurring polysaccharide polymers may be used for dissolution controlled release matrix systems. Furthermore, conventional processing techniques that were discussed for coating systems also can be used for matrix systems. 

Reaction of the ylide, generated from the phosphonium salt 578 (from the alcohol 577 and phosphine hydrobromide 504), with the polyene aldehyde 542 gives aleuria-xanthin acetate 579218). The methyl ester of the naturally occurring bixin 586 is formed by a combination of some carbonyl olefinations 279). The acetoxyaldehyde 580 is olefinated with methoxycarbonylmethylene-triphenylphosphorane 67 to the ( )-unsaturated ester 581. The latter is converted into the phosphonium salt 582 upon treatment with triphenylphosphine hydrobromide 504. The corresponding ylide of 582 is reacted with the dialdehyde 539 to the polyene aldehyde ester 583. The latter is reduced and converted into phosphonium salt 584. The corresponding ylide is now reacted in a third carbonyl olefination with 585 to give the methyl ester 586 279> (Scheme 98). 

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... 

In summary, a 6-substituted pterin was first identified as a structural component of the molybdenum cofactor from sulfite oxidase, xanthine oxidase and nitrate reductase in 1980 (24). Subsequent studies provided good evidence that these enzymes possessed the same unstable molyb-dopterin (1), and it seemed likely that 1 was a constituent of all of the enzymes of Table I. It now appears that there is a family of closely related 6-substituted pterins that may differ in the oxidation state of the pterin ring, the stereochemistry of the dihydropterin ring, the tautomeric form of the side chain, and the presence and nature of a dinucleotide in the side chain. In some ways the variations that are being discovered for the pterin units of molybdenum enzymes are beginning to parallel the known complexity of naturally occurring porphyrins, which may have several possible side chains, various isomers of such side chains, and a partially reduced porphyrin skeleton (46). 

The naturally occurring purines fall into 4 main groups. (1) Simple substituted derivatives of purine (1) such as adenine (2) and various 6-AT-substituted derivatives. (2) Monoxo-dihydropurines such as hypoxanthine (3), guanine (4), and isoguanine (5). f3) Dioxotetra-hydropurines such as xanthine (6) and methylated derivatives including the 3,7-dimethyl derivative theobromine (7), 1,3-dimethylxanthine or theophylline f8), and 1,3,7-trimethylxanthine or caffeine (9). (4) Trioxohexahydropurines such as uric acid (10). 

Many naturally occurring plant extracts are reputed to possess anti-irritant properties and have been recommended for use in cosmetic formulations. These include such diverse mixtures as tea tree oil, borage seed oil, Paraguay tea extract. Kola nut extract, oil of rosemary, and lavender oil. It is, however, difficult to standardize plant extracts and there may be a great deal of lot-to-lot variability in constituents. Understandably, this makes identification and isolation of any specific active constituent complex and laborious. The extracts may be oily or hydrophilic and contain compounds such as a-bisabolol, xanthines, polyphenols, and phytosterols.There is great potential in the use of plant extracts for irritation and sensitization reduction. This has been established within the cosmetic industry, and interest here has stimulated activity into reducing variability by more consistent cultivation techniques and more standardized extraction methods. 

In order to study the structure-activity relationships of phenolics as regards xanthine oxidase inhibition, berberine and eleven other naturally occurring phenolics were tested. The ICJ0 of berberine chloride was 170.74 pM, while that of quercetin (the most potent compound evaluated) was 7.23 pM [216]. 

Several authors have included one or more naturally occurring xanthine derivatives (caffeine, theobromine and theophylline) in their gas chromatographic separation of alkaloids. Lloyd et al.1 used a packed column with SE-30 on Chromosorb VI, so did Brochmann-Hanssen and... 

The first systematic investigation on the gas chromatographic separation of xanthine de-rivatives was published by Reisch and Walker. The naturally occurring xanthines, caffeine, theobromine and theophylline, as well as a number of derivatives, were gas chromatographed on an 1.5 % packed SE-30 column on Chromosorb W. In Table 20.1 the compounds are given and and in Figure 20.1 typical gas chromatograms. 

The natural products theophylline 34 (1,3-dimethylxanthine), theobromine 35 (3,7-dimethylxanthine) and caffeine 36 (1,3,7-trimethylxanthine) are derived from the lactam form of xanthine. Theophylline occurs in tea leaves and is a diuretic and a coronary vasodilator. Cocoa beans contain ca. 5% theobromine, which is a stronger diuretic than theophylline or caffeine. 

Some oxidations are mediated by hepatic enzymes localized outside the microsomal system. Alcohol dehydrogenase and aldehyde dehydrogenase, which catalyse a variety of alcohols and aldehydes such as ethanol and acetaldehyde, are found in the soluble fraction of the liver. Xanthine oxidase, a cytosolic enzyme mainly found in the liver and in small intestine, but also present in kidneys, spleen and heart, oxidizes mercaptopurine to 6-thiouric acid. Monoamine oxidase, a mitochondrial enzyme found in liver, kidney, intestine and nervous tissue, oxidatively deanoinates several naturally occurring amines (catecholamines, serotonin), as well as a number of drugs. 

Only six of the approximately 600 naturally occurring carotenoids [6] have so far been produced industrially these are three symmetrical C4o-carotenoids, p,p-carotene (3), cantha-xanthin (380), and astaxanthin (403), and three apo-p-carotenoids, ethyl 8 -apo-p-caroten-8 -oate (7), 8 -apo-p-caroten-8 -al (482) and the C33-ketone citranaxanthin (466). Table 1 gives the structural formulae of these pigments and their main applications. 

Another important naturally occurring pteridine is molybdopterin, apparently (9.28), which is the coenzyme of xanthine dehydrogenase, aldehyde oxidase, nitrate reductase, sulphite oxidase and presumably other enzymes that need both molybdenum and iron to function (Johnson and Rajagopolan, 1982). Xanthopterin, a co-lymphokine (p. 182), inhibits proliferation of lymphocytes (Ziegler 1983). 

Caffeine belongs to a family of naturally occurring compoimds called xanthines. The xanthines, in the form of their plant progenitors, are possibly the oldest known stimulants. They all, to varying extents, stimulate the central nervous system and the skeletal muscles. This stimulation results in an increased alertness, the ability to put off sleep, and an increased capacity for thinking. Caffeine is the most powerful xanthine in this respect. It is the main ingredient of the popular No-Doz keep-alert tablets. Although caffeine has a powerful effect on the central nervous system, not all xanthines are as effective. Thus, theobromine, the xanthine found in cocoa, has fewer central... 

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