2- -7-alkyl-hypoxanthines

In the early days of meteorite analysis, it was difficult to detect N-heterocycles later, the Murchison meteorite was shown to contain xanthine, hypoxanthine, guanine, adenine and uracil (about 1.3 ppm in total). This meteorite seems to contain various classes of basic and neutral N-heterocycles, as well as isomeric alkyl derivatives. 

With aquated Pt(II) compounds, numerous studies have revealed the kinetic preference of the 6-oxopurine N7 site [15,35]. In addition to the favorable electrostatic potential mentioned above [23] also steric factors seem to favor coordination to the guanine N7 site, in particular [36]. Estimated relative steric parameters (in parenthesis) suggest that the guanine N7 (1.00) and hypoxanthine N7 (1.03) atoms are the least sterically hindered binding sites in alkylated nucleobases, followed by the adenine N7 (1.17) and deprotonated hypoxanthine N1 (1.17) sites and the deprotonated N3 atoms of the different pyrimidine bases (1.39 for U, 1.44 for T, and 1.56 for C), while the adenine N1 (1.58) and... 

Abnormal bases (uracil, hypoxanthine, xanthine) alkylated bases in some other organisms, pyrimidine dimers... 

The alkylation of markedly acidic substances by lactim ethers is a reaction of the first type. Lactim ethers have been used as alkylating agents for imino compounds such as uric acid (39), xanthines, and hypoxanthine,08 and for the esterification of organic acids.09... 

Tetrahydropyranylation of hypoxanthine in DMSO obcurs with acidic catalysis and 2,3-dihydropyran, to produce l,9-bis(tetrahydropyran-2-yl)hypoxanthine (105) and the corresponding 1,7 isomer (106) (66JOC268s). Alkylation studies of 2-oxodihydropurine have been limited and no data are available for the 8-oxo isomer. Methylation of the 2-oxo derivative with methyl iodide in alkaline solution at 80 °C leads to the 7-methyl, then the 3,7-dimethyl derivatives. 

Free radical alkylation procedures have proved a useful route to alkylpurines which are not readily available by other methods. Thus 6-substituted purines including adenine and hypoxanthine may be converted into 8-methyl derivatives with t-butyl hydroperoxide in the presence of iron(II) ions and acid (74T2677), although small amounts of 2-methyl and 2,8-dimethyl derivatives were formed simultaneously. Adenosine and guanosine similarly furnished the corresponding 8-methyl derivatives with diacetyl peroxide (as a source of methyl radicals) and iron(II) ions (76T337). 

Useful precursors for the preparation of substituted hypoxanthine derivatives are alkyl 4(5)-aminoimidazole-5(4)-carboxylates. Thus, reaction of ethyl 4-amino-l-arylimida7ole-5-carb-oxylates with thioamides in the presence of a catalytic amount of formic acid gives 2-substituted 7-arylhypoxanthines, e.g. formation of l. °... 

Another C-alkylation of purines is the free-radical reaction with alkyl hydroperoxides catalyzed by iron(II) ions. This reaction has been applied to guanine, hypoxanthine, and adenine, as well as their nucleosides. A typical example is the 8-methylation of guanine to give 5 other examples are listed in Table 42. 

N2O3 formed by a third order reaction, can deaminate DNA bases yielding uracil from cytosine, xanthine from guanine, methyl cytosine from thymine and hypoxanthine from adenine [ 56 ]. Furthermore, it can react with secondary amines to yield carcinogenic N-nitrosoamines, which can damage DNA by alkylation, [57]. 

Alkylation of oxygenated purines in alkaline media, for example hypoxanthine, tends to occur both at amidic nitrogen and also at a flve-membered ring nitrogen, making selectivity a problem. Under neutral conditions, xanthines give 7,9-dialkylated qnatemary salts. The alkylation of 6-chloropurine illustrates the complexity in basic solntion both 7- and 9-snbstitution occurs, whereas reaction with dihydrofuran under acidic conditions is selective for N-9, perhaps as a thermodynamic product. ... 

Treatment of 1-ethyladenine 192 with 0.2 N aqueous NaOH caused rearrangement to iV-ethyladenine 194 with two by-products, hypoxanthine 196 and 1-ethylhypoxanthine 198, resulting from unusual hydrolytic deaminations of the intermediate 193 via 195 and 197, respectively. Rates increased with an increase in the pH of the medium. Similar results were also reported for the rearrangement of 7-alkyl-1 -methyladenines (94CPB382) (Scheme 63). 

Other DNA glycosylases recognize and remove a variety of damaged bases, including formamidopyrimidine and 8-hydroxyguanine (both arising from purine oxidation), hypoxanthine (arising from adenine deamination), and alkylated bases such as 3-methyladenine and... 

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