Nucleotides halogenation

Carboxylic acids can be protected as 2-haloethyl derivatives. These are reducible at different potentials depending on the kind and the number of halogen substituents at C2 (Fig. 40) [178]. This kind of protecting group has been employed in a nucleotide synthesis using the triester method ]179]. 

Although no new halogen-containing tetracyclines have been reported since the first survey (1), the gene responsible for the chlorination of tetracycline in Streptomyces aureofaciens (Fig. 3.24) has been cloned and the sequence of nucleotides determined (1651). The gene product is a 452 amino acid chlorination enzyme. 

The facile reaction of CAA and BAA with nucleosides and nucleotides is one example of many of the applications of the bifunctional reactivity of halogenated aldehydes and ketones in modification of biomolecules. In an early example of the extensive use of halogenated ketones as protease substrate analogues, l-V-tosylamido-2-phenylethyl chloro-methyl ketone (TPCK) 30 was synthesized as a chymotrypsin substrate analogue. Stoichiometric inhibition was accompanied by loss of one histidine residue as a result of alkylation by the chloromethyl moiety68. A host of similar analogues were subsequently prepared and used as selective enzyme inhibitors, in particular for the identification of amino acid residues located at enzyme active sites69. 

A large number of halogenated analogues are among the multitudinous synthetic nucleosides and nucleotides that have been prepared in the search for effective antiviral and antitumor agents. A comprehensive survey of this field is beyond the scope of this chapter. Selected examples will be given with an emphasis on the biochemical rationales involved. 

The facility with which the bromo, chloro and iodo analogues undergo reduction, with maintenance of the 5,6-double bond and replacement of the halogen by hydrogen, has been exploited for the electrochemical synthesis of 5-(3H)-uracil by conducting the reaction in tritiated water121). This procedure should be equally effective for the synthesis of labelled uracil nucleosides and nucleotides. 

As this chapter covers two years of the literature relating to the above area, it has been necessary to be somewhat selective in the choice of publications cited. Nevertheless, it is hoped that most significant developments have been noted. As in previous reports, attempts have been made to minimise the extent of overlap with other chapters, in particular those concerned with the synthesis of nucleic acids and nucleotides to which the chemistry of tervalent phosphorus esters and amides contributes significantly, the use of known halogen-ophosphines as reagents for the synthesis of phosphines (see Chapter 1), and the reactions of dialkyl- and diaryl-phosphite esters in which the contribution of the phosphonate tautomer, (R0)2P(0)H), is the dominant aspect, which are usually covered elsewhere in these volumes. 

Liu, M.-C., Luo, M.-Z., Mozdziesz, D. E., et al. (2001) Synthesis of halogen-substituted 3-deazaadenosine and 3-deazagunaosine analogues as potential antitumour/antiviral agents. Nucleosides Nucleotides Nucleic Acids, 20, 1975-2000. 

This review is limited to high resolution techniques for the analysis of proteins, but the use of analytical ITP has no such limitations. Such widely differing substances as ionizable lipids, halogen ions, trace metals, drugs, organic acids, nucleotides, and proteins can be analyzed by ITP (Al, E7). However, it is perhaps in the field of protein analysis that both the greatest potential and the greatest problems lie, because of the complexity of most natural protein mixtures. 

The method colmnn denotes procedures or processes used in the synthesis of the nucleotides. The Roman munerals refer to the phos-phorylating agent or system described in Table I. The other abbreviations denote the following AN = by way of anhydronucleotide intermediate(s) D = deamination Enz = enzymic hydrolysis pE] = hydrogenation HA = halogenation Hy = hydrolysis NA = W-alkylation NOx = iV-oxidation Ph = phosphorolysis of the activated nucleoside by the phosphate anion (seep. 369) R = by rearrangement RO = by ring-... 

Like their pyrimidine counterparts, these 3-halogenated adenosine-based nucleosides undergo conversion to the active triphosphate nucleotides (Fig. 42.25) after active transport into tumor cells. All are initially phosphorylated by... 

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