Pyrimidine and Purine Derivatives

Selective N-alkylation of 6-amino-2-thiouracil with different halides has been performed efficiently by use of MW-assisted methods in the presence of small amounts of DMF to improve energy transfer (Eq. 34 and Tab. 5.12). No reaction was observed under the same conditions in a thermoregulated oil bath. 

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As is well-known, nucleic acids consist of a polymeric chain of monotonously reiterating molecules of phosphoric acid and a sugar. In ribonucleic acid, the sugar component is represented by n-ribose, in deoxyribonucleic acid by D-2-deoxyribose. To this chain pyrimidine and purine derivatives are bound at the sugar moieties, these derivatives being conventionally, even if inaccurately, termed as pyrimidine and purine bases. The bases in question are uracil (in ribonucleic acids) or thymine (in deoxyribonucleic acids), cytosine, adenine, guanine, in some cases 5-methylcytosine and 5-hydroxymethylcyto-sine. In addition to these, a number of the so-called odd bases occurring in small amounts in some ribonucleic acid fractions have been isolated. 

For this reason dual terminology is in use for the aza analogs. The first, derived from the principal pyrimidine and purine derivatives by means of the prefix aza- is used almost exclusively in biochemical papers in organic chemistry is it used together with the systematic names) wherever it is desired to compare the properties of the natural bases and of their aza analogs. The systematic terminology is naturally used in the older literature where no biochemical aspects of the compounds were considered, and in some newer work of strictly chemical nature. Since the numbering of the substituents is in some cases different for the different systems, we shall discuss this in more detail later. ... 

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. 

Pyrimidine and purine derivatives serve in DNA and RNA to specify the genetic code. Imidazole derivatives enhance the catalytic activity of enzymes. We will consider these important heterocyclic derivatives in more detail in Chapters 23 and 24. 

The epoxidation of oxazolines with DMD by Adam and Hadjiarapoglou has been mentioned in (93TCC45) (Structure (101)). Epoxidations of pyrimidine and purine derivatives with DMD (93TL6313, 95T7561) as well as pyrazolo[l, 5-a]pyridine derivatives with Mn-TPP and Fe-TPP complexes using NaOCl as oxidant have also been reported (102)-(104) <89CPB1410>. 

It was previously shown that two reduced forms of NAD, viz. NADH and the dimer (NAD)2, may revert photochemically to the parent, enz3fmati-cally active NAD. Similar photochemical ability has been found for electrochemically generated dimers of pyrimidine and purine derivatives . In the presence of oxygen this photochemical oxidation is accompanied by formation of H2O2, and the superoxide radical O2 is an intermediate in the reaction". ... 

Kowalska et al. [48] have achieved a suitable TLC method for the separation of 19 pairs of the E-Z geometrical isomers of pyrazole, pyrimidine, and purine derivatives with potential cytokinin activity. These systems employed silica, silanized silica, silanized silica/Cu(II) cation, chemically bonded RP-8, and chemically bonded RP-18 as stationary phases, and a variety of binary (aqueous and nonaqueous) mobile phases. The quality of separations was evaluated by the use of three criteria — a,Rp, and ARp. The average numerical values of these criteria, calculated for the whole population of E-Z isomer pairs, were used to rank the investigated TLC systems in order of decreasing separating power. 

The most important derivatives of pyrimidines and purines are nucleosides Nucleosides are N glycosides m which a pyrimidine or purine nitrogen is bonded to the anomeric carbon of a carbohydrate The nucleosides listed m Table 28 2 are the mam building blocks of nucleic acids In RNA the carbohydrate component is d ribofuranose m DNA It IS 2 deoxy d ribofuranose... 

Section 28 2 Nucleosides are carbohydrate derivatives of pyrimidine and purine bases The most important nucleosides are derived from d ribose and 2 deoxy D ribose... 

Pyrimidine and purine themselves do not occur naturally, but many of their derivatives do. Before going too far-, we need to point out an important structural difference between derivatives that bear- —OH groups and those with —NH2 groups. The structure of a pyr imidine or purine that bear s an —NH2 group follows directly from the structure of the parent ring system. 

Section 28.2 Nucleosides are car bohydrate derivatives of pyrimidine and purine bases. 

The analogs of pyrimidine and purine bases can be derived by purely formal structural modifications or, more rationally, from the results of biochemical investigation. 

An important group of antimetabolites are the aza analogs of pyrimidine and purine bases which are theoretically derived by a replacement of the methine group of a pyrimidine or purine nucleus with a nitrogen atom. This replacement represents a relatively minor alteration of the structure of these substances as it does not change the functional groups, practically preserves the molecular weight, and produces almost isosteric compounds. The replacement of the methine... 

Under physiologic conditions, the amino and oxo tautomers of purines, pyrimidines, and their derivatives predominate. 

Analogous photoadditions have been observed on irradiation of pyrimidine and purine bases in ethers and amines. Irradiation of 1,3-dimethylur-acil (314) in tetrahydrofuran leads to the formation of 5- and 6-(tetrahydro-furan-2-yl)-5,6-dihydrouracils 315 and 316.261 Similarly, solvent adducts arising by way of initial hydrogen abstraction have been obtained on irradiation of pyrazine derivatives in diethyl ether or tetrahydrofuran.262 The... 

Figure 27.1 Three common nucleoside triphosphate derivatives that can be incorporated into oligonucleotides by enzymatic means. The first two are biotin derivatives of pyrimidine and purine bases, respectively, that can be added to an existing DNA strand using either polymerase or terminal transferase enzymes. Modification of DNA with these nucleosides results in a probe detectable with labeled avidin or streptavidin conjugates. The third nucleoside triphosphate derivative contains an amine group that can be added to DNA using terminal transferase. The modified oligonucleotide then can be labeled with amine-reactive bioconjugation reagents to create a detectable probe.

Sulfoxides have also been used in the synthesis of nucleoside analogs (Scheme 3.2). Chanteloup and Beau reported the synthesis of ribofuranosyl sulfoxide 13 and its use in the glycosylation of a series of silylated pyrimidine and purine bases.7 Although 16 is not an anomeric sulfoxide, its reaction with cytosine derivative 17 is conceptually related.8... 

Potentially tautomeric pyrimidines and purines are /V-alkylated under two-phase conditions, using tetra-n-butylammonium bromide or Aliquat as the catalyst [75-77], Alkylation of, for example, uracil, thiamine, and cytosine yield the 1-mono-and 1,3-dialkylated derivatives [77-81]. Theobromine and other xanthines are alkylated at N1 and/or at N3, but adenine is preferentially alkylated at N9 (70-80%), with smaller amounts of the N3-alkylated derivative (20-25%), under the basic two-phase conditions [76]. These observations should be compared with the preferential alkylation at N3 under neutral conditions. The procedure is of importance in the derivatization of nucleic acids and it has been developed for the /V-alkylation of nucleosides and nucleotides using haloalkanes or trialkyl phosphates in the presence of tetra-n-butylammonium fluoride [80], Under analogous conditions, pyrimidine nucleosides are O-acylated [79]. The catalysed alkylation reactions have been extended to the glycosidation of pyrrolo[2,3-r/]pyrimidines, pyrrolo[3,2-c]pyridines, and pyrazolo[3,4-r/]pyrimidines (e.g. Scheme 5.20) [e.g. 82-88] as a route to potentially biologically active azapurine analogues. 

New formulations are regularly commercialised. Studies on the action mechanism of 5-FU had a large influence on the development of other anti-tumour drugs derived from pyrimidine and purine. The 5-FU is industrially prepared at important tonnage by fluorination of uracil with elemental fluorine. 

Photochemical reactions of the purines and pyrimidines assume special significance because of the high molar extinction coefficients of the nucleic acids present in cells. Light is likely to be absorbed by nucleic acids and to induce photoreactions that lead to mutations.190 Both pyrimidines and purines undergo photochemical alterations, but purines are only about one-tenth as sensitive as pyrimidines. Photohydration of cytidine (Eq. 23-25) is observed readily. The reaction is the photochemical analog of the hydration of a,P-unsaturated carboxylic acids. Uracil derivatives also undergo photohydration. 

Aromatic compounds arise in several ways. The major mute utilized by autotrophic organisms for synthesis of the aromatic amino acids, quinones, and tocopherols is the shikimate pathway. As outlined here, it starts with the glycolysis intermediate phosphoenolpyruvate (PEP) and erythrose 4-phosphate, a metabolite from the pentose phosphate pathway. Phenylalanine, tyrosine, and tryptophan are not only used for protein synthesis but are converted into a broad range of hormones, chromophores, alkaloids, and structural materials. In plants phenylalanine is deaminated to cinnamate which yields hundreds of secondary products. In another pathway ribose 5-phosphate is converted to pyrimidine and purine nucleotides and also to flavins, folates, molybdopterin, and many other pterin derivatives. 

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