Boranophosphate Oligonucleotides: New Synthetic Approaches

Sergueev, Dmitri; Hasan, A.; Ramaswamy, M.; Shaw, Barbara Ramsay

doi:10.1080/07328319708006223

Cited by 30 publications

(35 citation statements)

References 4 publications

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“…Interestingly, the α‐ P ‐borane analogs of nucleoside triphosphates (e.g., NTPαB46 and dNPTαB39,45) are very good substrates for RNA and DNA polymerases and allow ready synthesis of BP RNA41 and BP DNA40,42,57 (i.e., RNA and DNA with P ‐boranophosphate internucleotide linkages) (Fig. 4).…”

Section: Advantages Of Functionalization With Boranophosphates: Codinmentioning

confidence: 75%

Reading, Writing, and Modulating Genetic Information with Boranophosphate Mimics of Nucleotides, DNA, and RNA

Shaw

Dobrikov

Wang

et al. 2003

Annals of the New York Academy of Sciences

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The P-boranophosphates are efficient and near perfect mimics of natural nucleic acids in permitting reading and writing of genetic information with high yield and accuracy. Substitution of a borane (-BH3) group for oxygen in the phosphate ester bond creates an isoelectronic and isosteric mimic of natural nucleotide phosphate esters found in mononucleotides, i.e., AMP and ATP, and in RNA and DNA polynucleotides. Compared to natural nucleic acids, the boranophosphate RNA and DNA analogs demonstrate increased lipophilicity and resistance to endo- and exonucleases, yet they retain negative charge and similar spatial geometry. Borane groups can readily be introduced into the NTP and dNTP nucleic acid monomer precursors to produce alpha-P-borano nucleoside triphosphate analogs (e.g., NTPalphaB and dNTPalphaB). The NTPalphaB and dNTPalphaB are, in fact, good to excellent substrates for RNA and DNA polymerases, respectively, and allow ready enzymatic synthesis of RNA and DNA with P-boranophosphate linkages. Further, boranophosphate polymer products are good templates for replication, transcription, and gene expression; boronated RNA products are also suitable for reverse transcription to cDNA. Fully substituted boranophosphate DNA can activate the RNase H cleavage of RNA in RNA:DNA hybrids. Moreover, certain dideoxy-NTPalphaB analogs appear to be better substrates for viral reverse transcriptases than the regular ddNTPs, and may offer promising prodrug alternatives in antiviral therapy. These properties make boranophosphates promising candidates for diagnostics; aptamer selection; gene therapy; and antiviral, antisense, and RNAi therapeutics. The boranophosphates constitute a versatile family of phosphate mimics for processing genetic information and modulating gene function.

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Section: Advantages Of Functionalization With Boranophosphates: Codinmentioning

confidence: 75%

Reading, Writing, and Modulating Genetic Information with Boranophosphate Mimics of Nucleotides, DNA, and RNA

Shaw

Dobrikov

Wang

et al. 2003

Annals of the New York Academy of Sciences

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“…The duplex formed with complementary DNA exhibited a T m that was 0.7 ˚C lower than the native DNA duplex, whilst the thermodynamic parameters of hybridisation (∆G˚, ∆H˚ and ∆S˚) and duplex conformation, as determined by CD spectroscopy, were very similar to the native duplex [85]. A similar template-directed primer extension reaction was also used to synthesise a 44-nucleotide stretch of mixed sequence, fully boranophosphate modified DNA [86]. Furthermore, α-borano dNTPs were shown to be compatible with the polymerase chain reaction (PCR), allowing effective amplification of DNA incorporating boranophosphates linkages, which has been used to develop a novel PCR sequencing method that is complementary to other sequencing methods [29,87].…”

Section: Boranophosphate Oligosmentioning

confidence: 99%

“…This significantly increases the likelihood that this modification will prove useful in antisense applications. Moreover, given that α-borano dNTPs are good substrates for DNA polymerases and PCR [29,[85][86][87], it would be interesting to see if boranophosphate DNA aptamers can be generated by in vitro selection, for binding to important protein targets. Even more intriguing is the possibility that boranophosphate RNA aptamers or ribozymes might be generated by a SELEX type procedure [43].…”

Section: Boranophosphate Oligosmentioning

confidence: 99%

Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications

Micklefield

2001

CMC

180

118

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Nucleic acids have been extensively modified by replacing the phosphodiester group or the whole sugar phosphodiester with alternative anionic, neutral and cationic structures. Several of these modified oligonucleotides exhibit improved properties including enhanced recognition and binding to RNA, duplex DNA and proteins. This has resulted in the development of new and more potent antisense and antigene agents, as well as aptamers. Furthermore, backbone modified oligonucleotides have also been used in the development of several alternative strategies, which rely on altogether different mechanisms of action and show significant promise for therapeutic intervention. In this review the latest advances in the synthesis and evaluation of the most promising backbone modified oligos will be discussed, with a view to their future as novel pharmaceuticals.

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“…Recently, because of the adaptathough achiral at phosphorus centers, have not provided an adtion of H-phosphonate chemistry for synthesis of boranophosvantage over the phosphorothioates. They are more susceptible phates (Sergueev et al, 1997), sufficiently long, nonstereoto some nucleases and less specific in inhibiting translation regular oligothymidine all-boranophosphates have become (Ghosh et al, 1993b). Thus, there remains an elevated interest available, also permitting exploration of the RNase H issue.…”

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confidence: 99%

Boranophosphates Support the RNase H Cleavage of Polyribonucleotides

Rait¹,

Shaw²

1999

Antisense and Nucleic Acid Drug Development

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Modification of the phosphodiester linkages in DNA by replacing one of the nonbridging oxygens with borane, BH3, produces an isoelectronic mimic of DNA called boranophosphates. Nonstereoregular oligodeoxyribonucleoside all-boranophosphates are shown here for the first time to elicit the RNase H hydrolysis of polyribonucleotides. We compared the ability of three types of dodecamers (dodecathymidine phosphate, phosphorothioate, and boranophosphate) to mediate the cleavage of poly(A) by Escherichia coli RNase H1. The rates of poly(A) hydrolysis induced by boranophosphates were 76-fold (at 20 degrees C) and 18-fold (at 30 degrees C) greater than the rates induced by dodecathymidine phosphate. In conjunction with the measured melting temperatures for each heteroduplex, carried out under the same conditions as the RNAse H cleavage experiments, the data establish an inverse relationship between the heteroduplex thermostability and the rate of poly(A) hydrolysis. Chromatographic analysis revealed another correlation: the higher the heteroduplex Tm, the higher the pApA:pApApA ratio in the corresponding hydrolysates. The specific content of these final products provides insight into the relative contribution of RNase H1 exonucleolytic/endonucleolytic mechanisms, with a low ratio for the lower melting heteroduplexes reflecting more endonucleolytic-type hydrolysis. In total, our data support the concept that antisense molecules with a weakened hybridization potential enhance the rate of hydrolysis of RNA in RNA-DNA hybrids.

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Boranophosphate Oligonucleotides: New Synthetic Approaches

Cited by 30 publications

References 4 publications

Reading, Writing, and Modulating Genetic Information with Boranophosphate Mimics of Nucleotides, DNA, and RNA

Reading, Writing, and Modulating Genetic Information with Boranophosphate Mimics of Nucleotides, DNA, and RNA

Backbone Modification of Nucleic Acids: Synthesis, Structure and Therapeutic Applications

Boranophosphates Support the RNase H Cleavage of Polyribonucleotides

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