Purine base synthesis

The exocychc nitrogens on cytosine and the purine bases must be protected during the synthesis. The search is ongoing for protecting groups that are subject to fewer side reactions and that can be removed more easily in the final deprotection step (34). 

Methotrexate belongs to the class of antimetabolites. As a derivative of folic acid it inhibits the enzyme dihydrofolate reductase resulting in a decreased production of thymidine and purine bases essential for RNA and DNA synthesis. This interruption of the cellular metabolism and mitosis leads to cell death. 

The mono-silylated or free acetamides, which are liberated during silylation with 22 a, can, furthermore, interfere with any subsequent reaction, e.g. with electrophiles. Thus in the one-pot/one-step silylation, Friedel-Crafts catalyzed, nucleoside synthesis starting from protected sugar derivatives and pyrimidine or purine bases, the mono- or bis-silylated amides such as 22 a can compete with less reactive silylated heterocycHc bases for the intermediate electrophilic sugar cation to form protected 1-acetylamino sugars in up to 49% yield [42, 47]. On silylation with trimethylsilylated urea 23 a the Hberated free urea is nearly insoluble in most solvents, for example CH2CI2, and thus rapidly precipitated [43]. 

Human tissues can synthesize purines and pyrimidines from amphibolic intermediates. Ingested nucleic acids and nucleotides, which therefore are dietarily nonessential, are degraded in the intestinal tract to mononucleotides, which may be absorbed or converted to purine and pyrimidine bases. The purine bases are then oxidized to uric acid, which may be absorbed and excreted in the urine. While little or no dietary purine or pyrimidine is incorporated into tissue nucleic acids, injected compounds are incorporated. The incorporation of injected [ H] thymidine into newly synthesized DNA thus is used to measure the rate of DNA synthesis. 

The purine base guanine is also formed in concentrated solutions of ammonium cyanide, i.e., the same substance which became known from Or6 s adenine synthesis. Or6, as well as Stanley Miller, was involved in a new series of experiments (Levi et al., 1999). The yield of guanine is, however, 10 10 times lower than that of adenine surprisingly, the synthesis is just as effective at 253 K as at 353 K. Low temperatures seem conceivable in certain parts of Earth as well as on the Jovian moon Europa (see Sect. 3.1.5) or in the Murchison meteorite. 

The purines from which uric acid is produced originate from three sources dietary purine, conversion of tissue nucleic acid to purine nucleotides, and de novo synthesis of purine bases. 

The chemistry, metabolism, and clinical importance of folic acid have been the subject of many excellent reviews (A7, Gil, H14, H20, Rl). Folic acid deficiency leads to a macrocytic anemia and leucopenia. These symptoms are due to inadequate synthesis of nucleic acid. The synthesis of purine bases and of thymine, required for nucleic acid synthesis, is impaired in folic acid deficiency. Detection of folic acid activity in biologic fluids and tissues is of the utmost importance it distinguishes between the various anemias, e.g., those due to vitamin Bi2 or folic acid deficiency. Because morphology of the abnormal red cell does not help in diagnosing vitamin deficiency, one must rely on assay methods for differential diagnosis. Treatment of pernicious anemia with folic acid has led to subacute combined degeneration of the spinal cord despite... 

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... 

Tetrahydrofolic acid (THF) is a co-en-zyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and required for cell growth and repUcation. Lack of THF leads to inhibition of cell proUferation. 

Inhibition of nucleobase synthesis (2). Tetrahydrofolic acid (THF) is required for the synthesis of both purine bases and thymidine. Formation of THF from folic acid involves dihydrofolate reductase (p. 272). The folate analogues aminopterin and methotrexate (ame-thopterin) inhibit enzyme activity as false substrates. As cellular stores of THF are depleted, synthesis of DNA and RNA building blocks ceases. The effect of these antimetabolites can be reversed Ltillmann, Color Atlas of Pharmacology 2000 Thieme All rights reserved. Usage subject to terms and conditions of iicense. 

Nitrogen donator in synthesis of purine bases, cytosine, GIcNAc, His, and Trp... 

These compounds inhibit synthesis of purine nucleotides, which are made up of purine bases and phosphorylated ribose. Both compounds must be transformed into nucleotides by adding a phosphoribosyl fragment. 

In connection with histidine, the work of Windaus and Knoop on the formation of methylimidazole from glucose must be mentioned on account of the possible synthesis in the animal body of both histidine and purine bases. 

Aspartic acid and arginines are important substrates for the biosynthesis of purine bases. They are also glycosylation sites in proteins. These reasons have been at the origin of the synthesis of their mono and difluoro analogues. 

The obvious similarity between the purine bases of DNA and pteridines, especially between guanosine and pterins, has encouraged extensive studies of the synthesis and properties of pteridine-containing nucleoside and nucleotides. Synthetic methods have naturally built upon established methods of nucleic acid synthesis. The primary property of use in applications of these compounds to DNA chemistry is fluorescence, which is very much greater for pteridines than for purines. 

Schultz and co-workers have described a crown-based synthesis of 406 purines varying at the C-2 and C-6 positions.14 This library was targeted for... 

PRPP is an "activated pentose" that participates in the synthesis of purines and pyrimidines, and in the salvage of purine bases (see p. 294). Synthesis of PRPP from ATP and ribose 5-phosphate is catalyzed by PRPP synthetase (ribose phosphate pyrophosphokinase, Figure 22.6). This enzyme is activated by inorganic phosphate (Pi) and inhibited by purine nucleotides (end-product inhibition). [Note The sugar moiety of PRPP is ribose, and therefore ribonucleotides are the end products of de novo purine synthesis. When deoxy-ribonucleotides are required for DNA synthesis, the ribose sugar moiety is reduced (see p. 295).]... 

A search for antimetabolites, i.e. analogues of essential metabolites that might displace the latter in vital processes, was proposed as a rational approach to the discovery of antibacterial agents, but it has had little success other than the achievements in the folic acid field (Section 1.06.6). Substances that resemble the components of nucleic acids have, however, had considerable success in the chemotherapy of cancer and of some virus diseases and in the suppression of the immune response. They may act by becoming incorporated in false nucleic acids or by blocking the synthesis of nucleic acids, nucleotides, nucleosides or of the pyrimidine and purine bases cytosine (88), thymine (89 R = Me), adenine (90) and guanine (91 X = CH). The simplest antimetabolites are analogues of these bases. 

All cells must be able to make pyrimidine and purine bases to be used in synthesis of nucleic acids and coenzymes. The pathway for synthesis of pyrimidine begins with aspartic acid and that for purines with glycine. In many organisms the pathway of purine formation is further enhanced because uric acid or a... 

Purine bases from ingested foods, or formed by catabolism of nucleic acids, are able to react with PRPP under the influence of phosphoribosyltransferases.3063 Two such enzymes are known to act on purines. One converts adenine to AMP (Fig. 25-17, step b) and also acts upon 5-aminoimidazole-4-carboxamide. This enzyme may be especially important to parasitic protozoa such as Leishmania, which lack the de novo pathway of purine synthesis (Fig. 25-15).278/306b... 

Purine nucleotides can be synthesized in three ways By de novo synthesis, by reconstruction from purine bases through the addition of a ribose phosphate moiety, or by phosphory-... 

In addition to the pathways for synthesis de novo, mammalian cells and microorganisms can readily form mononucleotides from purine bases and their nucleosides and to a lesser extent from pyrimidine bases and their nucleosides. In this way bases and nucleosides formed by constant breakdown of mRNA and other nucleic acids can be reconverted (or salvaged ) to useful nucleotides, and the energy expended by the cell in synthesizing the bases is retained. 

Bellon S, Ravanat J-L, Gasparutto D, Cadet J (2002) Cross-linked thymine-purine base tandem lesions synthesis, characterization, and measurement in y-irradiated isolated DNA. Chem Res Toxicol 15 598-606... 

Resistant to acids and bases and without a tendency to migrate, this group is stable for all the reactions employed in the synthesis of oligonucleotides. It is photolytically cleaved under a controlled pH without affecting the pyrimidine or purine bases [107, 108]. It has also been used as a photoremovable protecting group for the phosphate function [109]. 

Pd-catalysed allylation of amines proceeds smoothly. Allylamine (132) and di- and triallylamines are produced commercially by the Pd-catalysed reaction of ammonia with allyl alcohol using DPPB as a suitable ligand [69]. Allylic alcohols are rather unreactive substrates for 7r-allylpalladium complex formation under usual conditions. The intramolecular amination of 133 afforded the azaspiro ring 134 and the reaction was applied to the synthesis of perhydrohistrionicotoxin (135) [70]. Smooth Pd-catalyzed allylation of the purine base 136 gives 137, which is utilized for the synthesis of nucleosides [71]. 

Reagents A Convenient Route to sec- and tert- 6-Alkylpurines. Tetrahedron Lett. 1996, 37, 1285-1288. (c) Dvorakova, H. Dvorak, D. Holy, A. Synthesis of Acyclic Nucleotide Analogues Derived from 6-(sec- or tert-Alkyl) purines via Coupling of 6-Chloropurine Derivatives with Organocuprates. Collect. Czech. Chem. Commun. 1998, 63, 2065-2074. (d) Hocek, M. Holy, A. Perfluoroalkylation of 6-Iodopurines by Trimethyl(perfluoro-alkyl)silanes. Synthesis of 6-(Perfluoroalkyl)purine Bases, Nucleosides and Acyclic Nucleotide Analogues. Collect. Czech. Chem. Commun. 1999, 64, 229-241. 

The synthesis of various purine bases from hydrogen cyanide as the only carbon-containing substrate was documented by Orgel and coworkers [24]. The only stable precursor found in polymerization of hydrogen cyanide in concentrated (1-llmol/1) aqueous solutions is its tetramer, diaminomaleonitrile. It is easily formed in the reaction of hydrogen cyanide with ammonium cyanide (Figure 8.4). At the same time, in concentrated solutions of ammonium cyanide in the presence of ammonia, formamidine is formed ... 

Tetrahydrofolic acid (THF) is a coenzyme in the synthesis of purine bases and thymidine. These are constituents of DNA and RNA and are required for cell growth and replication. Lack of THF leads to inhibition of cell proliferation. Formation of THF from dihydrofolate (DHF) is catalyzed by the enzyme dihydrofolate reductase. DHF is made from folic acid, a vitamin that cannot be synthesized in the body but must be taken up from exogenous sources. Most bacteria do not have a requirement for folate, because they are capable of synthesizing it-more precisely DHF-ffom precursors. Selective interference with bacterial biosynthesis of THF can be achieved with sulfonamides and trimethoprim. 

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