Purine A-oxidation

Purines react slowly with peracids, such as perbenzoic acid (within a week), to yield the 1-oxide. An early report of the synthesis of a purine A -oxide by direct oxidation was the preparation of adenine 1-oxide (1) from the treatment of adenine with acetic acid/hydrogen peroxide. Related purine 1-oxides can be obtained from adenine 1-oxide by deamination. As most purine 7- and 9-oxides are not accessible by direct oxidation, the cyclization of the corresponding pyrimidine or imidazole precursors was undertaken. A review on heterocyclic A-oxides has appeared. ... 

Activation of a chloro substituent is accomplished using purine A-oxides. Thus, 2-chloroad-enine 1-oxide gives isoguanine 1-oxide (9) when treated with acid or base. ... 

Chemistry, synthesis, and biological evaluation of purine 7-A-oxides relative to nucleic acids 97H(44)573. 

Pyrimidines and purines derivatives act as bases and can be acquired through the diet. In particular, organ meats such as liver are a rich source of DNA and RNA. Most dietary purines are oxidized by enzymes to uric acid in the intestinal mucosa that is their excretory product in humans. The desease known as gout is related to high levels of uric acid in serum and the result of deposition of urate salts in various tissues. 

Oral administration of 42 to rats resulted in extensive reduction to trimethoprim106. The 1,4-di-N-oxide olaquindox (49), a substance used as a growth promotor in cattle breeding, pig husbandry and poultry farming, has been shown to be converted to a limited extent to the 4-mono-N-oxide in rats164, and compound 46 was readily reduced to N,N-diallylmelamine both in vivo and in vitro109. The anerobic reduction, in the presence of xanthine oxidase, of a series of purine N-oxides, such as adenine 1-N-oxide or guanine... 

The electrochemical behaviour and the adsorption of nucleic acid molecules and DNA constituents have been extensively studied over recent decades [1-6]. Electrochemical studies demonstrated that all DNA bases can be electrochemically oxidized on carbon electrodes [7-13], following a pH-dependent mechanism. The purines, guanine (G) and adenine (A), are oxidized at much lower positive potentials than the pyrimidines, cytosine (C) and thymine (T), the oxidation of which occurs only at very high positive potentials near the potential corresponding to oxygen evolution, and consequently are more difficult to detect. Also, for the same concentrations, the oxidation currents observed for pyrimidine bases are much smaller than those observed for the purine bases. Consequently, the electrochemical detection of oxidative changes occurring in DNA has been based on the detection of purine base oxidation peaks or of the major... 

Next, some typical examples will be presented of how a DNA-electrochemical biosensor is appropriate to investigate the DNA damage caused by different types of substances, such as the antioxidant agent quercetin (Scheme 20.1), an anticancer drug adriamycin (Scheme 20.2) and nitric oxide. In all cases, the dsDNA damage is detected by changes in the electrochemical behaviour of the immobilized dsDNA, specifically through modifications of the purinic base oxidation peak current [3,5,40]. 

The bacterial formamidopyrimidine-DNA glycosylase (alias Fpg or MutM) is a bifunctional base-repair enzyme (DNA glycosylase/AP lyase) that removes a wide range of oxidized purines from oxidatively damaged DNA. The crystal structures of the Fpg (MutM) enzymes from Thermus thermophilus, Lactococcus lactis Escherichia coli Bacillus stearothermophilus and the sequence similar endonuclease VIII (Nei) from E. all share the same... 

Examples of all the four purine iV-oxides are known. Purine 1-oxide may be prepared from purine and perbenzoic acid over two weeks (62JOC567), and adenine 1-oxide is similarly prepared from adenine over 2 days (58JA2759). On the other hand hypoxanthine 1-oxide is best obtained by deamination of adenine 1-oxide (66JOC966). Reaction of 5-amino-4-hydroxyformamidinoimidazole with carbon disulfide may be used to make 2-thioadenine 1-oxide which with alkaline peroxide provides a useful route to isoguanine 1-oxide (67JOC1151). 

Ionic as distinct from free radical oxidation (see Section 4.09.5.4) of purines leads to N-oxides. A major review of the chemistry of heterocyclic A-oxides including purine derivatives has been published (see Table 1) and should be consulted for more detailed information. Reagents most commonly used for direct oxidation of purines include hydrogen peroxide and various peracids but especially peracetic acid. 

A side-chain methylenamino group reacts with a nitroso group (introduced in situ) when the compound is heated with mineral acid [2466]. An unusual reaction occurred when the nitro-t-amine (103.4) was refluxed with acetic anhydride and zinc chloride the course of this reaction may involve an A -oxide [2039]. When an o-nitroalkylamine is heated with ethoxide, the two functions are converted into a 1-hydroxyimidazole ring [3004]. Nitrosation of the pyrim-idinone (103.5) involves several steps including a Fischer-Hepp rearrangement of an iV-nitroso to a ring-C-nitroso the final product is a 6-(4 -nitrophenyl-amino)purin-2-one [2667]. In a weakly basic medium, the nitroamine (103.6) is cyclized to either the benzimidazole (when R == H), or the benzimidazolone (when R H). 

There are few significant oxidations of purines apart from A-oxidations (27.1.1.4), but dimethyldioxirane gives good yields of 8-oxo compounds, possibly via the intermediacy of a 9,8- or 7,8-oxaziridine. C-8-Oxidation is an important process in vivo, for example with the oxomolybdoenzyme xanthine oxidase, where oxygen is introduced at C-8 via a mechanism about which there is still debate. 

Oral penciclovir has low (5%) bioavailability, while famciclovir is well absorbed orally and converted rapidly to penciclovir by side chain deacetylation and purine ring oxidation. The bioavailability of penciclovir is 70% after oral administration of famciclovir. Food slows absorption without reducing overall bioavailability. A small quantity of the 6-deoxy precursor but no famciclovir is detectable in plasma. The volume of distribution is -twice the volume of total-body water. 

The 7-A-oxides of purines related to nucleic acids their chemistry, synthesis, and biological evaluation , Fujii, T., Itaya, T., and Ogawa, K., Heterocycles, 1997, 44, 573. 

Et) which could be converted into the thiol (35 R = H, = Et) with a mixture of trifluoroacetic acid and phenol. Compound (35 R = H, R = Et) was used for the preparation of novel derivatives, c.g. [35, R = 5-(l-methyl-4-nitro)imidazoyl, R = Et]. Other 6-substituted purine derivatives, e.g. [36 R = Et, R = NH(CH2)3Me] were prepared by effecting nucleophilic displacement reactions on the thiomethylguanine, (35 R = Me, R = Et). The same reaction was applied to the synthesis of 6-substituted 9-vinylpurine systems, e.g. (36 R = CH=CH2, R == NEt2). Finally, 6-substituted purine N-oxides have been obtained by treatment of 6-chloropurine AT-oxides with nucleophilic agents in a reaction which is mechanistically analogous." ... 

Peracid A-oxidation of purines gives 1- and/or 3-oxides, depending on exact conditions. Adenine and adenosine give 1-oxides whereas guanine affords the 3-oxide. The 3-oxide of purine itself has been obtained via oxidation of 6-... 

In primary rat hepatocyte cultures 100 jiM ferric nitrilotriacetate induced five oxidation products of cellular DNA derived from both purines and pyrimidines (Abalea et al. 1999). Addition of increasing concentrations of myricetin (25-50-100 iM) simultaneously with iron prevented both lipid peroxidation and accumulation of oxidation products in DNA. Moreover, as an activation of DNA repair pathways, myricetin stimulated the release of DNA oxidation bases into culture media, especially of purine-derived oxidation products. The removal of highly mutagenic oxidation products from DNA of hepatocytes might correspond to an activation of DNA excision-repair enzymes by myricetin. This was verified by RNA blot analysis of DNA polymerase P gene expression, which was induced by myricetin in a dose-dependent manner. 

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