Purines phosphodiesterase

A number of other enzymes which catalyze the hydrolysis of phosphoesters are of biological importance. These include cyclic purine phosphodiesterase (little is known about its active site chemistry at present, but more shall be said about its biological role shortly) and the phosphatases. Acid and alkaline phosphatase catalyze the hydrolysis of phosphomonoesters to the corresponding alcohol and inorganic phosphate. Their pH optimums are 5.0 and 8.0, respectively hence their names. Both form covalent enzyme-substrate intermediates ... 

Caffeine in tea and coffee inhibits the phosphodiesterase that degrades cAMP. The resultant increase in cAMP levels, therefore, mimics the action of mediators such as the catecholamines that modulate adenylate cyclase. Caffeine and the related theophylline (both purine alkaloids, see Box 11.12) are thus effective stimulants of the CNS. 

The purine alkaloids caffeine, theobromine, and theophylline (Figure 6.135) are all methyl derivatives of xanthine and they commonly co-occur in a particular plant. The major sources of these compounds are the beverage materials such as tea, coffee, cocoa, and cola, which owe their stimulant properties to these water-soluble alkaloids. They competitively inhibit phosphodiesterase, resulting in an increase in cyclic AMP and subsequent release of adrenaline. This leads to a stimulation of the CNS, a relaxation of bronchial smooth muscle, and induction of diuresis, as major effects. These effects vary in the three compounds. Caffeine is the best CNS stimulant, and has weak diuretic action. Theobromine has little stimulant action, but has more diuretic activity and also muscle relaxant properties. Theophylline also has low stimulant action and is an effective diuretic, but it relaxes smooth muscle better than caffeine or theobromine. 

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). 

In a similar manner purine nucleotides including AMP and its a-anomer may be produced directly by reaction of the iV -benzoyl-9-bis(trimethylsilyl)adenine with 2,3-di-O-benzoyl-5-0-(diphenylphosphono)-D-ribofuranosyl bromide and deblocking the intermediate with lithium hydroxide and a phosphodiesterase from Trimeresums flavoviridis (b-78MI40903, p, 82l). This method however gives a low yield and can hardly be recommended. 

Several classes of enzyme degrade nucleic acids nucleases, phosphodiesterases, nucleotidases, nuclioside phosphorylases, and nucleosidases. The bases of purine nucleotides are degraded to form the nitrogenous waste product uric acid. 

The naturally occurring nucleoside analogues discussed in this section contain the IV-glycosyl linkage and either purine, pyrimidine, imidazole, diazepin, or indole rings. The purine nucleosides inhibit protein synthesis, RNA and DNA synthesis, and methyltransferases they have antimycoplasmal, antiviral, hypotensive, antifungal, antimycobacterial, and antitumor activities and induce sporulation (1—4). The pyrimidine nucleosides inhibit protein synthesis, virus replication, RNA and DNA synthesis, and cAMP phosphodiesterase. The imidazole nucleosides inhibit nucleic acid synthesis. The diazepin nucleosides inhibit adenosine deaminase (ADA). The indole nucleosides inhibit bacteria, yeast, fungi, and viruses. 

Various derivatives of the ring system have been synthesized as purine analogues, particularly as relatives of theophylline, a known bron-chodilator. Structure-activity relationships have been discussed for a series of 3-amino compounds. It seems that the most active compounds are substituted in the 6- and 8-positions by small alkyl groups. The presence of a substituent in the 5-position completely destroys activity. Patents claim a series of compounds, in particular 34, for the treatment of asthma and bronchospasm. " As the inhibition of cyclic AMP phosphodiesterase is thought to be responsible for the bronchodilator action of theophylline, compound 34 was tested and found to be a potent... 

Isosteres of purine (e.g. pyrazolo- and pyrolopyrimidines) are of importance as building units of pharmaceuticals. Examples are allopurinol 46 (gout therapeuticum [153]) and sildenafil 47 (inhibitor of type V cGMP phosphodiesterase, Viagra). 

Inhibitors of phosphodiesterase increase the intracellular level of cyclic AMP, which is associated with increased myocardial contractility. One of the first POE-inhibitors so studied is theophylline (21), an important drug in the treatment of asthma. Its actions have been extensively reviewed.81 Several recent studies have indicated that it might stimulate contractility also by adenosine receptor antagonism.82 In patients with chronic obstructive pulmonary disease, theophylline (14 mg/kg, p.o.) improved cardiac performance.83,94 severe adverse side effects were observed.85,96 Many derivatives of theophylline and other purine analogs were prepared and tested as PDE-inhibitors and cardiac stimulants, some of them being several times more active than... 

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