Over the past decade, there has been extensive work in the design, synthesis and application of nuclease-resistant oligonucleotide analogues for therapeutics, research and diagnostic use.75 The research in this area arises from the fact that most forms of diseases are the result of a function of protease enzymes, and most therapeutic drugs are directed toward these proteins. Antisense technology deals with the destruction of disease-causing proteins. This is done by inhibiting the particular protein's production through hydrogen bonding of nuclease-resistant oligonucleotides. More specifically, this therapy relies upon the hybridization of sequence-specific hydrogen bonding of oligonucleotides to RNA and single-stranded DNA so as to interfere in the translation process (protein synthesis).76 In this regard, research has been carried out in modification or replacement of the basic structure of the nucleic acids, e.g. phosphorus backbone, sugar or base moieties.
Oligonucleotides, in which non-bridging oxygen atoms are replaced by bor-ane (BH3) groups, constitute a very important class of modified nucleic acids.4 These compounds seek to take advantage of the fact that the BH3 group is isoelectronic with atomic oxygen in natural oligonucleotides, and isoelectronic and isostructural with the oligonucleotide methyl phosphonates, which are nuclease-resistant. The structures of several boron-containing dinucleotide analogues are shown in Figure 2.34.77
On the other hand, the a-borano triphosphates are good substrates for DNA polymerases and incorporation of boranophosphates into DNA causes an increase in the resistance to exo- and endo-nucleases as compared to non- modified DNA.3a In addition, important new diagnostic applications have been reported in the areas of polymerase chain reaction (PCR) sequencing76 and DNA diagnostics using boronated DNA. Figure 2.35 summarizes some of the applications of boronated nucleosides, nucleotides and oligonucleotides.78
Selective silver staining
Boronated nucleosides, nucleotides and oligonucleotides
Stable DNA/RNA probes
Anti-metabolite, anti-viral and anti-tumor agents
Figure 2.35 Applications of boronated nucleosides, nucleotides and oligonucleotides
Although considerable efforts have been devoted to taking advantage of the boranophosphate linkage, numerous limitations are inherent in the use of the BH3 moiety, especially in chemical syntheses. The highly reducing nature of this group can cause base degradation. It has been reported that the borane group is incompatible with some commonly used protecting groups in modified oligo-nucleotide synthesis.29 Likewise, the BH3 moiety has severe toxicity implications in that borohydrides, boranocarbonates and amineboranes typically have LD50 values in the tens of mg/kg by ip injection in mice. The syntheses and properties of biologically important molecules that contain substituted boranes of the form BH2X (X = COOR, C(O)NHR, CN, etc.) have been investigated extensively.1,79 The use of these substituted boranes in oligonucleotide modification may ameliorate some of the problems encountered with the unsubsti-tuted boranonucleic acids. Since the boron analogue of glycine, H3NBH2COOH, was found to have a very low toxicity (LD50 >2000 mg/ kg),30 there is a good chance that the use of substituted boranonucleosides will result in less toxic products.
Hosmane eta/. have synthesized modified oligonucleotides containing P—BH2X (X = CN, COOMe and CONHEt) linkages and characterized them by spectroscopic and analytical techniques.80 The corresponding structures are shown in Figure 2.36.
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