Polynucleotides interaction with nucleosides

Especially attractive was the possibility to connect nucleosides, as has been realized, for instance, with the hexathymidine 141 and with the elongated and alternating strands 142 and 143. These compounds represent artificial oligonucleosides, which may interact with natural polynucleotides or nucleic acids. On treatment with Cu(i), 142 and 143 gave the double-helical complexes 144 and 145, respectively, inside-out analogues of double-stranded nucleic acids, which may be termed deoxy-... 

Treatment of 5-deoxy-5-halogeno nucleosides of adenine and uracil with trimethylamine yielded the corresponding 5-deoxy-5-trimethylammonium salts, whose interaction with anionic polynucleotides was then examined. Various A -alkyl, A -cycloalkyl, and iV-alkaryl derivatives of 3-amino-3-deoxy-and 3, 5 -diamino-3, 5 -dideoxy-adenosine have been prepared from the amino-sugar nucleosides the 3 -benzylamino derivative gave the unusual oxazolidine derivative (52). ° ... 

Interaction of Polynucleotides with Nucleosides, Nucleotides, and Purines... 

More than 100 enzymes are Involved in the biosynthesis,modification,polymerisation, or degradation of nucleosides and nucleotides, many more act upon the polynucleotides, I A and RNA, or they require nucleotide coenzymes and nucleotides like ATP as cosubstrates or allosteric effectors. Besides their specific catalytic functions all these proteins should exhibit certain common modes of protein - nucleotide Interactions because the amino, Imlno, carbonyl, hydroxyl, and phosphate groups of nucleotides represent but a limited array of substituents capable to Interact with protein residues (Figure 1). There are, however, surprisingly few systematic studies on the structural origins of nucleotide specificity. 

In contrast to Mg + and Mn +, which stabilize secondary structures in DNA and RNA, Cu + destabilizes DNA and RNA double helices, and this is attributed to the ability of copper to bind to the nucleic acid bases. Chao and Kearns have recently explored the possibility that this binding, as detected by electron and nuclear magnetic resonance spectroscopy, might be used to probe certain structural features of nucleic acid molecules, such as the looped out regions of tRNAs. The nature of the Cu complexes formed with nucleosides and nucleotides varies with the specific nucleic acid derivatives used and also the pH. Thus, in the pH range 8.5—10.0, copper forms a water-soluble complex with the ribose OH groups of the ribonu-cleosides and 5 -ribonucleotides, but these complexes cannot form with any of the deoxynucleosides or the 2 - and 3 -ribonucleotides. It is suggested that copper(ii) could stabilize unusual polynucleotide structures or interactions in certain enzymatic systems the latter could, for example, be responsible for translational errors in the RNA,DNA polymerase system which are known to be induced by transition metals. 

The DNA and RNA polymerase reactions, as well as the reverse transcriptase and polynucleotide phosphorylase reactions, proceed with inversion of configuration at Pa of the nucleoside triphosphate (45-50). Thus, an uneven number of displacements at phosphoms is involved in the chemical reaction mechanism, and the stereochemistry provides no evidence for the involvement of a covalent nucleotidyl-enzyme as an intermediate on the catalytic pathway. No other evidence for such an intermediate is available. Therefore, it must be concluded that the physicochemical requirements for nucleotidyl group transfer, substrate recognition, and movement along the template are derived fiom binding interactions between the enzyme and its template and substrate rather than through nucleophilic catalysis. This is also true of polynucleotide phosphorylase and other nucleotidyltransferases that catalyze reactions of polynucleotides (51, 52). 

That being so, some of the common nucleases which degrade ordinary polynucleotides could well have evolved to interact primarily with polynucleotides whose nucleoside components are anti. It is of interest, in this regard, that the diesterases from spleen and snake venom, and micrococcal nuclease, do not digest poly F, which is syn also that the specificity of pancreatic RNase for the natural substrates - uridine and cytidine - is based on their normal anti conformation. 

The identification of DNA as a primary target for metal-based drugs, especially cisplatin, has focused attention on the interactions of metal complexes with nucleic acid constituents, which include the simple purine and pyrimidine bases and their nucleoside and nucleotide derivatives. The structures, with abbreviations, are represented in Appendix 1. Simple complexes can represent models for cross links in DNA, which can be studied in more detail with small polynucleotides, from the simpler dinucleotides to oligonucleotides and this topic is covered in Section 4.4. There has been extensive use of substituted purines and pyrimidines as models for the DNA bases and in the examination of steric and electronic effects. The structures of many of these analogues are also collected in Appendix 1. 

---