Synthesis, Duplex Stabilization and Structural Properties of a Fluorinated Carbocyclic LNA Analogue

Seth, Punit P.; Pallan, Pradeep S.; Swayze, Eric E.; Egli, Martin

doi:10.1002/cbic.201200669

Cited by 19 publications

(16 citation statements)

References 25 publications

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“…In particular, S -cEt-modified oligonucleotides reduced hepatotoxicity relative to 2′,4′-BNA/LNA-modified one without decreasing gene-silencing potency . In addition, among various carba-LNA analogues developed to date, − duplex-forming ability of ( R )-Me-cLNA was higher than that of ( S )-Me-cLNA, which suggested that the properties of oligonucleotides significantly depended on the configuration of 7′-position on carba-LNA. Furthermore, the 8′ R -methyl derivative of EoDNA showed lower duplex-forming ability and higher nuclease resistance compared to the other EoDNA and methylene-EoDNA derivatives possibly because of 1,3-diaxial interaction between the 8′-methyl group and 3′-phosphodiester .…”

Section: Introductionmentioning

confidence: 99%

Synthesis of 2′-C,4′-C-Methyleneoxy-Bridged Thymidine Derivatives and Properties of Modified Oligonucleotides

et al. 2019

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2′,4′-Bridged nucleic acid (2′,4′-BNA) analogues are used for therapeutic oligonucleotides, owing to their excellent hybridizing ability with complementary RNA and high resistance toward enzymatic degradation. We developed 2′,4′-BNA analogues with oxygen atoms at 6′-positions (e.g., EoNA and EoDNAs) and demonstrated that the presence of 6′-oxygen atoms in the bridge structure could show positive effect on the properties of the modified oligonucleotides. Herein, we designed and synthesized 7′-methyl derivatives of methyleneoxy-bridged 2′-deoxyribonucleic acid (MoDNA), possessing a five-membered bridge with 6′-oxygen atom via radical cyclization for the bridge construction. The synthesized monomers were incorporated into the oligonucleotides by solid-phase oligonucleotide synthesis. The MoDNA-modified oligonucleotides showed high affinity toward single-stranded RNA and double-stranded DNA, as well as excellent resistance toward nuclease compared with the corresponding natural oligonucleotide.

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Section: Introductionmentioning

confidence: 99%

Synthesis of 2′-C,4′-C-Methyleneoxy-Bridged Thymidine Derivatives and Properties of Modified Oligonucleotides

et al. 2019

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“…The 2′-F-RNA-modified oligonucleotides are, however, more sensitive to nucleolytic degradation than other 2′-modified oligonucleotides; moreover, these monomers are recognized, albeit poorly, by human RNA polymerases at high concentrations. , Hence, chemically modified building blocks that retain the advantages of 2′-F-RNA with additional features to overcome these limitations have the potential to improve pharmacological properties of oligonucleotides. A number of fluorine-containing building blocks have been synthesized and evaluated in the context of oligonucleotide-based therapeutics. − However, to the best of our knowledge, none of these modifications have been made with all four nucleobases. As nucleotide pharmacology in a therapeutic oligonucleotide like siRNA depends on both sequence and position, it is necessary to have all four nucleosides with same ribosugar modification to evaluate its therapeutic potential …”

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confidence: 99%

Synthesis and Biophysical Characterization of RNAs Containing 2′-Fluorinated Northern Methanocarbacyclic Nucleotides

et al. 2019

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2′-Fluorinated Northern methanocarbacyclic (2′-F-NMC) nucleosides and phosphoramidites, based on a bicyclo[3.1.0]hexane scaffold bearing all four natural nucleobases (U, C, A, and G), were synthesized to enable exploration of this novel nucleotide modification related to the clinically validated 2′-deoxy-2′-fluororibonucleotides (2′-F-RNA). Biophysical properties of the 2′-F-NMC-containing oligonucleotides were evaluated. A duplex of 2′-F-NMC-modified oligonucleotide with RNA exhibited thermal stability similar to that of the parent RNA duplex, 2′-F-NMC-modified oligonucleotides had higher stability against 5′-and 3′-exonucleolytic degradation than the corresponding oligonucleotides modified with 2′-F-RNA, and 2′-F-NMC-modified oligonucleotides exhibited higher lipophilicity than the corresponding RNA oligonucleotides as well as those modified with 2′-F-RNA.

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“…Also other fluorinated nucleic acids such as 2’-fluorocyclohexenyl nucleic acid (F-CeNA, Fig. 1) [27] and other modifications [28–31] have been analyzed on their antisense properties.…”

Section: Introductionmentioning

confidence: 99%

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

Frei

Katolik

Leumann

2019

Beilstein J. Org. Chem.

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Here we present the synthesis, the biophysical properties, and the RNase H profile of 6’-difluorinated [4.3.0]bicyclo-DNA (6’-diF-bc4,3-DNA). The difluorinated thymidine phosphoramidite building block was synthesized starting from an already known gem-difluorinated tricyclic glycal. This tricyclic siloxydifluorocyclopropane was converted into the [4.3.0]bicyclic nucleoside via cyclopropane ring-opening through the addition of an electrophilic iodine during the nucleosidation step followed by reduction. The gem-difluorinated bicyclic nucleoside was then converted into the corresponding phosphoramidite building block which was incorporated into oligonucleotides. Thermal denaturation experiments of these oligonucleotides hybridized to complementary DNA or RNA disclosed a significant destabilization of both duplex types (ΔT m/mod = −1.6 to −5.5 °C). However, in the DNA/RNA hybrid the amount of destabilization could be reduced by multiple insertions of the modified unit. In addition, CD spectroscopy of the oligonucleotides hybridized to RNA showed a similar structure than the natural DNA/RNA duplex. Furthermore, since the structural investigation on the nucleoside level by X-ray crystallography and ab initio calculations pointed to a furanose conformation in the southern region, a RNase H cleavage assay was conducted. This experiment revealed that the oligonucleotide containing five modified units was able to elicit the RNase H-mediated cleavage of the complementary RNA strand.

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Synthesis, Duplex Stabilization and Structural Properties of a Fluorinated Carbocyclic LNA Analogue

Cited by 19 publications

References 25 publications

Synthesis of 2′-C,4′-C-Methyleneoxy-Bridged Thymidine Derivatives and Properties of Modified Oligonucleotides

Synthesis of 2′-C,4′-C-Methyleneoxy-Bridged Thymidine Derivatives and Properties of Modified Oligonucleotides

Synthesis and Biophysical Characterization of RNAs Containing 2′-Fluorinated Northern Methanocarbacyclic Nucleotides

Synthesis, biophysical properties, and RNase H activity of 6’-difluoro[4.3.0]bicyclo-DNA

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