NUCLEOSIDES. XIV. SYNTHESIS OF 2'-DEOXY-2'-FLUOROURIDINE<sup>1</sup>

Codington, John F.; Doerr, Iris L.; Praag, Dina Van; Bendich, Adrianne; Fox, Jack J.

doi:10.1021/ja01485a036

Cited by 34 publications

(16 citation statements)

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“…Eight of the now approved 13 oligonucleotide drugs feature the PS modification in the backbone and all four approved siRNA therapeutics: ONPATTRO ® (patisiran, 2018), GIVLAARI ® (givosiran, 2019), OXLUMO ® (lumasiran, 2020) and LEQVIO ® (inclisiran, 2020) have 2'-OMe modifications [18][19][20][21] (https:// www.oligotherapeutics.org/20th-anniversary-of-rna-interference-in-mammalian-cells/). Interestingly, both 2'-OMe [22] and PS [23] date back to the 1960s and constitute the earliest modifications reported by chemists along with the synthesis of 2'-deoxy-2'-fluoro-nucleosides (FRNA) [24].…”

Section: Introductionmentioning

confidence: 99%

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Liczner¹,

Duke²,

Juneau³

et al. 2021

Beilstein J. Org. Chem.

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Over the past 25 years, the acceleration of achievements in the development of oligonucleotide-based therapeutics has resulted in numerous new drugs making it to the market for the treatment of various diseases. Oligonucleotides with alterations to their scaffold, prepared with modified nucleosides and solid-phase synthesis, have yielded molecules with interesting biophysical properties that bind to their targets and are tolerated by the cellular machinery to elicit a therapeutic outcome. Structural techniques, such as crystallography, have provided insights to rationalize numerous properties including binding affinity, nuclease stability, and trends observed in the gene silencing. In this review, we discuss the chemistry, biophysical, and structural properties of a number of chemically modified oligonucleotides that have been explored for gene silencing.

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Section: Introductionmentioning

confidence: 99%

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Liczner¹,

Duke²,

Juneau³

et al. 2021

Beilstein J. Org. Chem.

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“…Work on chemical modification of nucleosides and nucleotides was initiated in the 1960s. The earliest examples are 2′-deoxy-2′fluoro-uridine (2′-F U), 1 nucleoside phosphorothioates (PSOs), 2 and 2′-O-methyl (2′-O-Me) RNA 3 (Figure 1). Interestingly, these first-generation modifications figure prominently in the backbones of oligonucleotide drugs approved over the last 20 years and therapeutic candidates currently in phase I to III clinical trials in the US.…”

Section: Introductionmentioning

confidence: 99%

Re-Engineering RNA Molecules into Therapeutic Agents

2019

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Conspectus Efforts to chemically modify nucleic acids got underway merely a decade after the discovery of the DNA double helix and initially targeted nucleosides and nucleotides. The origins of three analogues that remain staples of modification strategies and figure prominently in FDA-approved nucleic acid therapeutics can be traced to the 1960s: 2′-deoxy-2′-fluoro-RNA (2′-F RNA), 2′-O-methyl-RNA (2′-OMe RNA), and the phosphorothioates (PS-DNA/RNA). Progress in nucleoside phosphoramidite-based solid phase oligonucleotide synthesis has gone hand in hand with the creation of second-generation (e.g., 2′-O-(2-methoxyethyl)-RNA, MOE-RNA) and third-generation (e.g., bicyclic nucleic acids, BNAs) analogues, giving rise to an expanding universe of modified nucleic acids. Thus, beyond site-specifically altered DNAs and RNAs with a modified base, sugar, and/or phosphate backbone moieties, nucleic acid chemists have created a host of conjugated oligonucleotides and artificial genetic polymers (XNAs). The search for oligonucleotides with therapeutic efficacy constitutes a significant driving force for these investigations. However, nanotechnology, diagnostics, synthetic biology and genetics, nucleic acid etiology, and basic research directed at the properties of native and artificial pairing systems have all stimulated the design of ever more diverse modifications. Modification of nucleic acids can affect pairing and chemical stability, conformation and interactions with a flurry of proteins and enzymes that play important roles in uptake, transport or processing of targets. Enhancement of metabolic stability is a central concern in the design of antisense, siRNA and aptamer oligonucleotides for therapeutic applications. In the antisense approach, uniformly modified oligonucleotides or so-called gapmers are used to target a specific RNA. The former may sterically block transcription or direct alternative splicing, whereas the latter feature a central PS window that elicits RNase H-mediated cleavage of the target. The key enzyme in RNA interference (RNAi) is Argonaute 2 (Ago2), a dynamic multidomain enzyme that binds multiple regions of the guide (antisense) and passenger (sense) siRNAs. The complexity of the individual interactions between Ago2 and the siRNA duplex provides significant challenges for chemical modification. Therefore, a uniform (the same modification throughout, e.g., antisense) or nearly uniform (e.g., aptamer) modification strategy is less useful in the pursuit of siRNA therapeutic leads. Instead, unique structural features and protein interactions of 5′-end (guide/Ago2MID domain), seed region, central region (cleavage site/Ago2 PIWI domain), and 3′-terminal nucleotides (guide/Ago2 PAZ domain) demand a more nuanced approach in the design of chemically modified siRNAs for therapeutic use. This Account summarizes current siRNA modification strategies with an emphasis on the regio-specific interactions between oligonucleotide and Ago2 and how these affect the choice of modification and optimization of siRNA e...

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“…Pyrimidine O2,2'-cyclonucleosides have successfully been used as intermediates for the specific inversion or replacement of the ribose O(2')-hydroxyl group. Thus spongouridine (3-fl-D-arabinofuranosyluracil) could be obtained by hydrolysis of O2,2'-cyclouridine with dilute acid (Brown, Todd & Varadarajan, 1956) and a similar ring opening by treatment with anhydrous hydrogen halide gave the various 2'-halogeno-2'-deoxyuridines (Codington, Doerr, Praag, Bendich & Fox, 1961). From the reactivity of these cyclonucleosides one would expect the molecules to be strained to some extent.…”

Section: Introductionmentioning

confidence: 99%

The crystal and molecular structure of O2,2'-cyclouridine. Influence of O(2)–C(2') cyclization on the sugar conformation of pyrimidine nucleosides

Suck¹

1973

Acta Crystallogr Sect B

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NUCLEOSIDES. XIV. SYNTHESIS OF 2'-DEOXY-2'-FLUOROURIDINE¹

Cited by 34 publications

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Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Re-Engineering RNA Molecules into Therapeutic Agents

The crystal and molecular structure of O2,2'-cyclouridine. Influence of O(2)–C(2') cyclization on the sugar conformation of pyrimidine nucleosides

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NUCLEOSIDES. XIV. SYNTHESIS OF 2'-DEOXY-2'-FLUOROURIDINE1

Cited by 34 publications

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Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Beyond ribose and phosphate: Selected nucleic acid modifications for structure–function investigations and therapeutic applications

Re-Engineering RNA Molecules into Therapeutic Agents

The crystal and molecular structure of O2,2'-cyclouridine. Influence of O(2)–C(2') cyclization on the sugar conformation of pyrimidine nucleosides

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NUCLEOSIDES. XIV. SYNTHESIS OF 2'-DEOXY-2'-FLUOROURIDINE¹