Synthesis of New Classes of Boron-Containing Nucleotides

Lin, Jinlai; Shaw, Barbara Ramsay

doi:10.1081/ncn-100002335

Cited by 18 publications

(16 citation statements)

References 15 publications

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“…In recent studies, we have expanded the class of boranophosphates to previously unknown phosphate species. In addition to P ‐borano analogs of cyclic mononucleotides80–82 and diphosphates,83–84 a number of different double‐modified phosphodiesters modified with a borane and either a methyl or a heteroatom were chemically synthesized82,85–89 (Fig. 8).…”

Section: Molecular Family Of Boranophosphatesmentioning

confidence: 99%

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: Molecular Family Of Boranophosphatesmentioning

confidence: 99%

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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“…Their structures were confirmed by 1D- and 2D- 1 H NMR, 31 P NMR, FAB-MS, and HRMS. It has to be pointed out that the 31 P NMR of boranophosphoramidate 24 (or 9 ) has a characteristic broad peak around δ 92 ppm . This result does not agree with the reported 31 P NMR around δ 105 ppm by Baraniak et al in a recent communication on the synthesis of boranophosphoramidate in which neither 1 H NMR nor HRMS data were provided 21b…”

Section: Resultsmentioning

confidence: 83%

“…The reaction was completed within 30 min as monitored by 31 P NMR, where the two peaks corresponding to the two diastereomers (two singlets, δ = 139.5, 139.7 ppm) for intermediate 6 became a broad peak centered at δ 118.0 ppm corresponding to the borane complex 8 . Treatment of 8 with H 2 O resulted in the formation of desired compound boranophosphoramidate 9 , whose 31 P NMR showed a characteristic broad peak at δ 93.5 ppm …”

Section: Resultsmentioning

confidence: 99%

Synthesis of Nucleoside Boranophosphoramidate Prodrugs Conjugated with Amino Acids

Shaw

2005

J. Org. Chem.

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[structure: see text] Nucleoside boranophosphates and nucleoside amino acid phosphoramidates have been shown to be potent antiviral and anticancer agents with the potential to act as nucleoside prodrugs. A combination of these two types of compounds results in a boranophosphoramidate linkage between the nucleoside and amino acid. This new class of potential prodrugs is expected to possess advantages conferred by both types of parent compounds. Two approaches, specifically the H-phosphonate and oxathiaphospholane approaches, are described here to synthesize nucleoside boranophosphoramidate prodrugs conjugated with amino acids. The H-phosphonate approach involves a key intermediate, silylated nucleoside amino acid phosphoramidite 6, prepared from a series of reactions starting from nucleoside H-phosphonate in the presence of condensing reagent DPCP. Due to the lengthy procedure and the difficulties in removing DPCP from the final products, we switched to the oxathiaphospholane approach in which the DBU-assisted oxathiaphospholane ring-opening process constituted a key step for the generation of nucleoside amino acid boranophosphoramidates 24. We demonstrate that this key step did not cause any measurable C-racemization of boranophosphorylated amino acids 22. Diastereomers of compounds 24a-f were separated by RP-HPLC. An "adjacent"-type mechanism is proposed to explain the diastereomer ratio in the final products obtained via the oxathiaphospholane approach. A tentative assignment of configuration for the diastereomers was carried out based on the mechanism, molecular modeling, and (1)H NMR. Conclusively, the oxathiaphospholane methodology proved to be more facile and efficient than H-phosphonate chemistry in the preparation of the nucleoside amino acid boranophosphoramidate analogues that are promising as a new type of antiviral prodrugs.

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“…The synthesis and properties of some nucleotides and oligonucleotides containing double-modified phosphates, i.e. boranophosphothioate [27] and the uncharged boranomethylphosphonate [28], have also been reported.…”

Section: Boranophosphatesmentioning

confidence: 98%

Nucleotide analogues as probes for DNA polymerases

Jung

Marx

2005

Cell. Mol. Life Sci.

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Transmission of the genetic information from the parental DNA strand to the offspring is crucial for the survival of any living species. In nature, all DNA synthesis in DNA replication, recombination and repair is catalyzed by DNA polymerases and depends on their ability to select the canonical nucleobase pair from a pool of structurally similar building blocks. Recently, a wealth of valuable new insights into DNA polymerase mechanisms have been gained through application of carefully designed synthetic nucleotides and oligonucleotides in functional enzyme studies. The applied analogues exhibit features that differ in certain aspects from their natural counterparts and, thus, allow investigation of the involvement and efficacy of a chosen particular aspect on the entire complex enzyme mechanism. This review will focus on a depiction of the efforts that have been undertaken towards the development of nucleotide analogues with carefully altered properties. The different approaches will be discussed in the context of the motivation and the problem under investigation.

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Synthesis of New Classes of Boron-Containing Nucleotides

Cited by 18 publications

References 15 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

Synthesis of Nucleoside Boranophosphoramidate Prodrugs Conjugated with Amino Acids

Nucleotide analogues as probes for DNA polymerases

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