Adenosine compounds

Amino-3 -deoxyadenosine. 3 -Amino-3 -deoxyadenosine (17) is elaborated by Cordyceps militarise Aspergillus nidulanSe and Helminthosporium (3,4). The biosynthesis proceeds direcdy from adenosine. Compound (17) inhibits RNA polymerase, but not DNA polymerase, and replaces the adenosyl residue at the 3 -terminus of tRNA. Phenylalanyl-(3 -amino-3 -deoxyadenosyl)-tRNA has acceptor but not donor activity (31,32). Compound (17) also inhibits retroviral RNA-dependent DNA polymerase (33). 

The susceptibilities of some of these fluorinated purine nucleosides to the action of enzymes are now described. In contrast to the inertness of the 2 -deoxy-2 -fluoro- and 3 -deoxy-3 -fluorocytidine analogs 739, 744, and 821 towards cytidine deaminase, the adenosine compounds 867, 883, and 906 are readily deaminated - by the adenosine deaminase in erythrocytes and calf intestine, but the resulting (deaminated) inosine compounds (from 867 and 883), as well as 888, are highly resistant - to cleavage by purine nucleoside phosphorylase (to give hypoxanthine base for the first two). The reason was discussed. Both 867 and 883 can form the 5 -triphosphates, without deamination, in human erythrocytes or murine sarcoma cells in the presence of 2 -deoxycoformycin, an adenosine deaminase inhibitor, but... 

Concerning human studies, only three reports have been reported (for review see Burnstock et al., 2000). Bleehen and Keele (1977) reported observations on the algogenic actions of adenosine compounds on blister base preparations. Coutts et al. (1981) injected ATP, ADP, AMP, adenosine, adenine and inosine intradermally. The area of erythema induced by the injection was delineated at 30 s. and again after a further 4.5 min when the size of the response was maximal. ATP, ADP and AMP evoked weal and flare responses in the skin in a dose-dependent manner. The rank order of potency was ATP > ADP > AMP other metabolites were apparently inactive. Injections of ATP and high doses of ADP produced a sensation of persistent pain. 

Bleehen, T. and Keele, C.A. Observations on the algogenic actions of adenosine compounds on human blister base preparation, Pain 1977, 3, 367-377. 

Fig. 2.2 Scatter plot of -TAS° versus AH° values for the adenosine A3 receptor ligands (n = 11) studied obtained in hA3 CHO cells (a). Scatter plot of a typical series of adenosine compounds (n = 85) for the A, A2A, A2B and A3 adenosine receptor subtypes (b). Full and open symbols indicate antagonists and agonists, respectively. All points lie on a same regression line. The two dashed lines indicate the loci of the points representing possible combinations of AH° and -TAS° values giving rise to the two different equilibrium constants indicated (KA = 104 and KA = 1011 M )...

FIGURE 14.9 Plasma concentration of 7-deaza-2 -C-[14C]methyl-adenosine (Compound A) (ng/mL open circle) and total 14C levels (ng Eq/mL filled circle) after oral administration of 0.02mg/kg (-100 nCi) 14C-Compound A to dogs (n = 2). (Adapted from Sandhu, P. et al., Drug Metab. Dispos., 32, 1254, 2004. With permission.)... 

The nucleotide anhydride, adenosine 5 -triphosphate (24), when digested with aqueous barium hydroxide, gives a complex mixture containing such products as adenine, adenosine, adenosine 2 -, 3 -, and 5 -phosphates, adenosine 5 -pyrophosphate, and adenosine 2 (or 3 ),5 -diphosphate. - In addition, a nucleotide was foimd in this digest whose structure proved - to be that of adenosine 3 5 -cyclic phosphate (25). This component did not consume metaperiodate, and was degraded enzymically to adenosine 5 -phosphate (26) and adenosine 3 -phosphate (27), without the formation of adenosine 2 -phosphate. Hydrolysis of (25) with an acidic ion-exchange resin did, however, produce the 2 - and 3 -phosphates of adenosine. Compound (25) possessed only one phosphoryl dissociation, and showed a ratio of nucleoside to phosphate of 1 1, which, along with a molecular-... 

As important as nucleotides of adenosine are to bioenergetics that is not the only indispensable part they play m biology The remainder of this chapter describes how these and related nucleotides are the key compounds m storing and expressing genetic information... 

Adenosine triphosphate (ATP) is a key compound m biological energy storage and delivery... 

The D arabinose analog of adenosine is an anitiviral agent (vidarabine) used to treat con junctivitis and shingles Wnte a structural formula for this compound... 

Phosphorus. Eighty-five percent of the phosphoms, the second most abundant element in the human body, is located in bones and teeth (24,35). Whereas there is constant exchange of calcium and phosphoms between bones and blood, there is very Httle turnover in teeth (25). The Ca P ratio in bones is constant at about 2 1. Every tissue and cell contains phosphoms, generally as a salt or ester of mono-, di-, or tribasic phosphoric acid, as phosphoHpids, or as phosphorylated sugars (24). Phosphoms is involved in a large number and wide variety of metaboHc functions. Examples are carbohydrate metaboHsm (36,37), adenosine triphosphate (ATP) from fatty acid metaboHsm (38), and oxidative phosphorylation (36,39). Common food sources rich in phosphoms are Hsted in Table 5 (see also Phosphorus compounds). 

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

Phosphodiesterase Inhibitors. Because of the complexity of the biochemical processes involved in cardiac muscle contraction, investigators have looked at these pathways for other means of dmg intervention for CHF. One of the areas of investigation involves increased cycHc adenosine monophosphate [60-92-4] (cAMP) through inhibition of phosphodiesterase [9025-82-5] (PDE). This class of compounds includes amrinone, considered beneficial for CHF because of positive inotropic and vasodilator activity. The mechanism of inotropic action involves the inhibition of PDE, which in turn inhibits the intracellular hydrolysis of cAMP (130). In cascade fashion, cAMP-catalyzed phosphorylation of sarcolemmal calcium-channels follows, activating the calcium pump (131). A series of synthetic moieties including the bipyridines, amrinone and milrinone, piroximone and enoximone, [77671-31-9], C22H22N2O2S, all of which have been shown to improve cardiac contractiUty in short-term studies, were developed (132,133). These dmgs... 

Adenosine triphosphate (ATP) Common energy-donating molecule in biochemical reactions. Also an important compound in transfer of phosphate groups. 

ATP Adenosine triphosphate. Chemical energy generated by substrate oxidations is conserved by formation of high-energy compounds such as adenosine diphosphate (ADP) and adenosine triphosphate (ATP) or compounds containing the thioester bond. 

Several toxic compounds act by inhibiting the oxidation of carbohydrates or by inhibiting the formation of adenosine triphosphate (ATP), a molecule that... 

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