Nucleotide derivatives

The following example illustrates the selective cleavage of a 2 -benzoate in a nucleotide derivative. 

An enzyme on the cell surface that metabolizes nucleotide derivatives by hydrolytically cleaving one or more phosphate groups. 

Figure 1.56 Nucleotide derivatives have additional functions in vivo beyond their role in oligonucleotide construction.

Terminal transferase labeling was originally developed using radiolabeled (typically 32P) nucleoside triphosphates (Roychoudhury et al., 1979 Tu and Cohen, 1980). Later, the technique was extended to the use of nonradioactive nucleotide derivatives (Kumar et al., 1988). 

Figure 27.9 Biotin-ll-dUTP is perhaps the most popular nucleotide derivative used for enzymatic biotinylation of oligonucleotides. The 11 designation refers to the number of atoms in its spacer arm.

Two aldehydic nucleotide derivatives have found use as affinity labels. The magnesium salt of (64), formed by oxidation of ATP with periodate, is a competitive inhibitor of pyruvate carboxylase with respect to [Mg. ATP2-],100 and (65), obtained from the / -anomer of 5-formyluridine-5 -triphosphate on treatment with alkali, is a non-competitive and reversible inhibitor of DNA-dependent RNA polymerase from E. coli.101 In each case, addition of borohydride gives stoicheiometric covalent linkage of the nucleotide to the enzyme, with irreversible inactivation. It is thought that condensation with lysine occurs to give a Schiff s base intermediate, which undergoes subsequent reduction. 

Coenzyme A is another adenine nucleotide derivative, with its primary functional group, a thiol, some distance away from the nucleotide end of the molecule. This thiol plays an important role in biochemistry via its ability to form thioesters with suitable acyl compounds (see Box 7.18). We have seen how thioesters are considerably more reactive than oxygen esters, with particular attention being paid to their improved ability to form enolate anions, coupled with thiolates being excellent leaving groups (see Box 10.8). 

The currency unit for energy in biochemical reactions is the nucleotide derivative ATP, adenosine... 

Electron donating a-substituents favour the non-Kolbe reaction but the radical intermediates in these anodic processes can be trapped during co-electrolysis with an alkanoic acid. Anodic decarboxylation of sugar uronic acids leads to formation of the radical which is very rapidly oxidised to a carbonium ion, stabilised by the adjacent ether group. However, in the presence of a tenfold excess of an alkanoic acid, the radical intermediate is trapped as the unsymmetrical coupling product [101]. Highly functionalised nucleotide derivatives such as 20 will couple successfully in the mixed Kolbe reaction [102], Other examples include the co-electrolysis of 3-oxa-alkanoic acids with an alkanoic acid [103] and the formation of 3-alkylindoles from indole-3-propanoic acid [104], Anodic oxidation of indole-3-propanoic acid alone gives no Kolbe dimer [105],... 

Nucleotides and nucleosides have emerged as important molecules in medicinal chemistry. In the 1950s, Elion and Hitchings discovered that 6-mercaptopurine had antitumor properties. This pioneering discovery opened the door for many subsequent studies of nucleotide derivatives as therapeutics. Acyclovir (8.3), a nucleoside that lacks two carbon atoms of its ribose ring, is effective in the treatment of herpes infections. Allopurinol, a purine derivative, is useful in the treatment of gout. 

This chapter focuses primarily on endogenous molecules as nonmessenger targets for drug design. There are many such molecules. As discussed earlier, amino acid derivatives, lipids (eicosanoids), nucleoside/nucleotide derivatives, and carbohydrates all afford heterocyclic leads for drug design. The discussion will not be repeated here. 

This sub-section is devoted to nucleotide derivatives that may participate in biosynthesis of certain polymers containing carbohydrate. They are generally included among the sugar nucleotides, although their structures differ somewhat from those of the glycosyl esters of nucleoside 5 -pyrophosphates so far discussed. 

Nucleoside 5 -phosphorothioates have also been employed as activated nucleotide derivatives for synthesis of pyrophosphates.321 The interaction of tributylammonium 2, 3 -di-0-benzoyluridine 5 -phosphorothioate (73) with silver a-D-glucopyranosyl and a-D-galac-topyranosyl phosphates in pyridine solution, with subsequent de-benzoylation, gave the corresponding glycosyl esters in 60-70% yield. This procedure can probably be classified as a variant of the mixed-anhydride method, the driving force of the reaction being the formation of insoluble silver sulfide. 

In bacteria, primary glycosyl nucleotides include14 22 UDP-Glc, as well as other nucleotide derivatives of the same monosaccharide. Important representatives of this class are16"21,23"25 dTDP-Glc and17"19,21,26 29 CDP-Glc, which serve as precursors for a number of secondary glycosyl nucleotides, whereas similar enzymic reactions have not been demonstrated for GDP-Glc,1819,21,30 and ADP-Glc17 19,21-31"38 seems to participate only in the biosynthesis of bacterial glycogen, a subject that is beyond the scope of this article. 

The information that determines amino-acid sequence in a protein to be synthesized is contained in the DNA of a cell nucleus as a particular sequence of nucleotides derived from adenine, guanine, thymine, and cytosine. For each particular amino acid there is a sequence of three nucleotides called a codon. 

Table 10 The Nucleic Bases, Their Proton Ionization Constants (pit,), and the Nomenclature of Their Nucleoside and Nucleotide Derivatives...

---