Of nucleosides and nucleotides

Michelson, A M. 1963, The Chemistry of Nucleosides and Nucleotides, Academic Press New York London... 

These were originally prepared by Khorana as selective protective groups for the 5 -OH of nucleosides and nucleotides. They were designed to be more acid-labile than the trityl group because depurination is often a problem in the acid-catalyzed removal of the trityl group. Introduction of p-methoxy groups increases the rate of hydrolysis by about one order of magnitude for each p-methoxy substituent. For 5 -protected uridine derivatives in 80% AcOH, 20°, the time for hydrolysis was... 

Michelson, A. M. The chemistry of nucleosides and nucleotides. London Academic Press 1963... 

A. Mononucleotides.—A new journal has appeared in the past year consisting of abstracts of papers published in the nucleotide and nucleic acid fields. The use of nucleosides and nucleotides as potential therapeutic agents has been reviewed. Nucleotides which have been prepared recently using conventional methods of phosphorylation include those derived from 6-methylthiopurine ribonucleoside (la), 5-methylsulphonyluridine (lb), l-(jS-D-ribofuranosyl)-2-pyrimidone (Ic), 3-(jS-D-ribofuranosyl)-4-pyrimidone (Id), and various thionucleosides. - O-Phosphorylated 3 -amino-3 -deoxythymidine (2a) and 5 -amino-5 -deoxythymidine (2b)... 

Phenylglyoxal and alkoxyphenylglyoxals react selectively with the guanine moiety of nucleosides and nucleotides in phosphate buffer (pH 7.0) at 37°C for 5-7 min to give the corresponding fluorescent derivatives [12-15], as shown in Figure 6. Other nucleic acid bases and nucleotides (e.g., adenine, cytosine, uracil, thymine, AMP, CMP) do not produce derivatives under such mild reaction conditions. The fluorescent derivative emits chemiluminescence on oxidation with di-methylformamide (DMF) and H202 at pH 8.0-12 [14, 15],... 

Product distributions obtained on esterification of nucleosides and nucleotides under basic conditions throw further light on factors affecting selective reactivity. p-Toluenesulfonylation of adenosine 5 -monophosphate in aqueous alkali yielded exclusively (in 54-61% yield) the 2 -p-toluenesulfonate.107 Lack of reaction at HO-3 was attributed either to formation of a phosphoric p-toluenesulfonic anhydride, which sterically protected this hydroxyl group, or to the higher acidity of HO-2. It has been shown that the acidic site (with pKa 12.5) in adenosine is associated with the presence of both HO-2 and HO-3, as replacement of either of these by hydrogen, or of HO-2 by methoxyl, results in loss of this acidity.108 Inductive effects, or the sta-... 

Purine ribonucleotide biosynthesis Pyrimidine ribonucleotide biosynthesis Salvage of nucleosides and nucleotides Sugar-nucleotide biosynthesis and conversions Other... 

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. 

Comparatively little was previously known about photoaddition reactions to unsaturated substrates of different structure. Elements of water add to the A5 6 in the pyrimidine ring of 1,3-dimethyluracil (CXXXYII)301 and probably of nucleosides and nucleotides of cytosine261,307 upon irradiation with ultraviolet light to give products such as CXXXVIII. CXXXVIII reverts to CXXXVII under the influence of acid, alkali, or heat. 

M. Ikebara and H. Miki, Studies of nucleosides and nucleotides. LXXXH Cyclonucleosides. (39). Synthesis and Properties of 2 -halogeno-2 -deoxyadenosines, Chem. Pharm Butt. 26 2449 (1978). 

The purines and pyrimidines are relatively stable compounds with considerable aromatic character. Nevertheless, they react with many different reagents and, under some relatively mild conditions, can be completely degraded to smaller molecules. The chemistry of these reactions is complex and is made more so by the fact that a reaction at one site on the ring may enhance the reactivity at other sites. The reactions of nucleic acids are largely the same as those of the individual nucleosides or nucleotides, the rates of reaction are often influenced by the position in the polynucleotide chain and by whether the nucleic acid is single or double stranded. The reactions of nucleosides and nucleotides are best understood in terms of the electronic properties of the various positions in the bases.26 33 Most of the chemical reactions are nucleophilic addition or displacement reactions of types that are discussed in Chapters 12 and 13. 

Owing to the great biological importance of this class of compounds, the 13C NMR spectra of a considerable number of nucleosides and nucleotides and their aglycones have been reported in the literature [147,428, 460, 676, 735, 748-760]. As demonstrated by the spectra of flavin adenine dinucleotide (Fig. 5.9), the 13C NMR spectra of nucleosides and nucleotides have two groups of signals ... 

The assignments of the purine resonances [460, 749, 751, 758, 759, 761] of proton broadband-decoupled 13C NMR spectra of nucleosides and nucleotides are made using the following aids [749, 761] Correlation with the signals of the parent bases and analogous nucleosides or nucleotides comparison of the 13C NMR spectrum with that of a specifically analogue correlations of the chemical shift values with the 7r-electron densities [749, 761] and, in addition, proton off-resonance decoupling, which affords the identification of quaternary carbon atoms. 

A further aid in assigning vicinal cis hydroxy groups in carbohydrate residues of nucleosides and nucleotides makes use of boric acid as a complex shift reagent at various pH values [686]. In the presence of boric acid and at pH > 7 all complexing... 

Studies on the kinetic behaviour of nucleoside and nucleotide complexes are less common than those on structural aspects. This arises because of the rapid rates of the formation and dissociation reactions, requiring NMR or temperature-jump relaxation measurements. The number of species that can coexist in solution also hinders interpretation. The earlier kinetic studies have been reviewed by Frey and Stuehr.127 Two important biological reactions of the nucleotides are phosphoryl and nucleotidyl group transfers. Both reactions are catalytic nucleophilic reactions and they both require the presence of a divalent metal ion, in particular Mg2+. Consequently, one of the main interests has been in understanding the catalytic mechanism of the metal ion involvement. This has mainly involved studies on related non-enzymic reactions.128... 

The introduction of methoxy substituents increases the ease of removal of trityl groups under acid conditions, but also decreases the selectivity for the primary hydroxyl group [377]. As a compromise, the monomethoxytrityl and dimethoxy-trityl groups found widespread use for the protection of primary positions of glycosides (see, e.g. Ref. [378]) and, especially for the OH-5 function of nucleosides [377]. The use of 6-nitroquinoline instead of pyridine was described [379] to improve the selectivity of monomethoxytritylation of nucleosides and nucleotides bearing free amino groups. A general and rapid procedure was developed for the preparation and isolation of 5 -0-dimethoxy trityl derivatives [380]. 

Two-dimensional planar electrophoresis was first used in 1951 (8), while electrophoresis was coupled with thin-layer chromatography (TLC) in 1964 to separate mixtures of nucleosides and nucleotides (9). These techniques were novel and led to other great discoveries, but did not survive the test of time, and they are no longer commonly used. TLC-electrophoresis in particular was an awkward technique to... 

As mentioned by Tipson,10 the question arises as to whether ultraviolet absorption spectra of the type described112-114 can serve as proof for the positional assignment of the carbohydrate moiety on the pyrimidine ring of nucleosides. The increasing usage of spectrophotometry in the isolation, and in structural and enzymic studies, of nucleosides and nucleotides warrants a detailed consideration of this technique. The studies described above,112 114 for example, may be open to question (despite the fact that the conclusions were correct), since the pH of the curves selected was not predicated upon the ionization constants of the compounds under investigation. A series of comprehensive spectral studies of nucleosides of nucleic acids, their parent pyrimidines, and related compounds have been reported,87-110 and much of the following discussion is derived from them. 

Electrophoresis in the CZE mode takes place in an open tube and in a free solution without any separation matrix in the capillary. The separation is based on the mass/charge ratio of the analytes. It is appropriate for the separation of nucleosides and nucleotides. It is not well suited for medium to large oligonucleotides, because their mass/charge ratio tend to be smaller. The use of a separation matrix becomes necessary for these species. Various capillary systems, including bare fused silica capillaries and surface-coated capillaries, have been used in CZE. 

For recent reviews of the chemistry of the nucleic acids and related topics see B. Lythgoe, Chemistry of Nucleosides and Nucleotides, Ann. Repts. on Progress Chem. (Chem. Soc. London), 41, 200 (1945) R. S. Tipson, The Chemistry of the Nucleic Acids, Advances in Carbohydrate Chemistry, 1, 193 (1945) A. R. Todd, Synthesis in the Study of Nucleotides, J. Chem. Soc., 647 (1946) B. Lythgoe, Chemistry of Adenine Nucleotide Coenzymes, Ann. Repts. on Progress Chem. (Chem. See. London), 42, 175 (1946) B. Lythgoe and A. R. Todd, Structure and Synthesis of Nucleotides, Symposia Soc. Expll. Biol. I. Nucleic Acid, 1947, 15 A. R. Todd, Synthase de Nucleotides, Bull. soc. chim. France, 1948,933 B. Lythgoe, Some Aspects of Pyrimidine and Purine Chemistry," Quart. Revs., 3, 181 (1949). 

Bromo- and chloroacetaldehyde react readily with adenine and cytosine, either free or as constituents of nucleosides and nucleotides (Figure 5)63. The etheno adducts so formed are highly fluorescent, a discovery that has made this reaction a very valuable research... 

The chapter begins with a discussion of the structure of nucleosides and nucleotides. Then the structure of the nucleic acids, DNA and RNA. the polymers formed from nucleotide monomers, is presented. The function of these polymers in the replication, transcription, and translation of genetic information is briefly addressed. Next, the organic chemistry involved in determining the sequence of DNA is presented. Finally, the synthesis of small DNA molecules in the laboratory is discussed. 

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