Pyrimidine Phosphodiesterases

The existence of photoreversible, but not of heat-reversible, absorbance change in irradiated poly dI dC was taken to prove that the photoproducts are entirely dimers (in contrast to those in poly C irradiations where the product is almost entirely the hydrate82a). It was possible to detect dimers of uracil as well as those of cytosine, by means of the much slower photoreversal of uracil dimers. In the acid hydrolysates of irradiated dl-dC, both uracil dimers and uracil could be identified. Enzymatic hydrolysis (snake venom phosphodiesterase) does not split pyrimidine dimers, and the products of such hydrolysis of irradiated tritium-labeled poly dl dC contained trinucleotides shown by radioactivity to contain cytosine dimers. Thymine dimers were formed in the photolysis of the poly dA dT, and were detected and assayed by the same methods. The yield of thymine dimers in irradiated poly... 

Some compounds having quite similar pyrazolo[4,3- pyrimidine structures have been claimed in the patent literature to be potent phosphodiesterase inhibitors. Some are claimed to act also upon female sexual dysfunctions. 

Plenty of biological activities have been attributed to derivatives of ring systems 1-50 in the patent and published literature. New substituted pyrazolo[4,3- pyrimidines have been synthesized and claimed to be useful for treatment of male erectile dysfunction due to the inhibitory action they exerted on phosphodiesterase enzymes <1998EPP995750, 2000USP6066722>. Diverse biological activities have been attributed to pyrazolo[3,4-, pyrimidines... 

Substituted pyrazolo[l,5-a]pyrimidines are selective inhibitors of adenosine 3, 5 -Cyclic monophosphate (CAMP) phosphodiesterases in vitro (74JMC645 75JMC460). 

Similar to pyrazolo[l,5-a]pyrimidines certain pyrazolo[3,4-4]pyrimidines exhibit phosphodiesterase inhibitory action (68MI1). Herbicidal activity of pyrazolo[3,4-4]pyrimidines has also been observed (79MIP354186). 

A) Inhibition of platelet phosphodiesterases (PDEs) [91]. Quercetin and myricetin potentiated the anti-aggregatory action of prostacyclin (PGI2), a potent stimulator of platelet adenylate cyclase synthesised by the vascular endothelium, on ADP-induced platelet aggregation in washed human platelets, and the elevation of platelet cyclic adenosine monophosphate (cAMP) elicited by PGI2 [89,92,93]. These effects are probably due to an inhibition of PDEs. As suggested by Ferrell and co-workers [92], this inhibition arises from the similarity between the pyranone ring of flavonoids and the pyrimidine ring of adenine. 

Several 5-aminothieno[3,4-d]pyrimidine-2,4-diones 358 showed phosphodiesterase inhibitory activity superior to that of theophylline (90MI9 91MI3). 

Fig. 2.8. Nearest neighbour analysis and quantitative depurination analysis of a defined product from a primed synthesis reaction. When radioactive dATP (or dGTP) is used in the primed synthesis, depurination analysis will yield pyrimidine tracts each of which terminate in a radioactive 3 -phosphate. Thus only those depurination products which lie 5 -adjacent to the labelled nucleotide will be labelled. Each depurination product will be labelled to the same specific activity thus greatly simplifying the quantitation. Digestion of the labelled product with a mixture of micrococcal nuclease and bovine spleen phosphodiesterase yields the nucleoside 3 -monophosphates. Identification of the labelled products (by paper electrophoresis at pH 3.S) gives the nearest neighbours to the labelled substrate.

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). 

Many thieno[2,3-<7]pyrimidine derivatives were patented as phosphodiesterase inhibitors (1990PCT08113, 1991JAP225485, 1993PCT03040, 1997USP5679683,... 

Enzymological and pharmacological properties of 2-(2-methylpyridin-4-yl)methyl-4-(3,4,5-trimethoxyphenyl-8-(pyrimidin-2-yl)methoxy-l,2-dihydro-l-oxo-2,7-naphthyridine-3-carboxylic add methyl ester hydrochloride, a new phosphodiesterase type 5 inhibitor, were studied in vitro and in vivo (2002MI6). 

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. 

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