Novel conformationally constrained 2′-<i>C</i>-methylribonucleosides: synthesis and incorporation into oligonucleotides

Vejlegaard, Kim; Wegeberg, Christina; McKee, Vickie; Wengel, Jesper

doi:10.1039/c7ob02663c

Cited by 9 publications

(8 citation statements)

References 26 publications

(30 reference statements)

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“…Numerous other LNA analogues have been constructed including, but not limited to, 2'-N-guanidino,4'-C-ethylene (GENA) (Figure 7I) [166], sulfonamide-bridged (suNA) (Figure 7J) [167], 2'-Me LNAs (Figure 7K) [168,169], 6'-Me-2'-O,4'-Cethylene-bridged (6'-Me-ENA) (Figure 7L) [170], and various triazole-linked LNA (Figure 7M) [171,172] that have all shown the ability to modulate LNA properties.…”

Section: Sugar and Nucleobase Modifications 2'-o-alkyl Modificationsmentioning

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: Sugar and Nucleobase Modifications 2'-o-alkyl Modificationsmentioning

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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“…It is worth noting that after the computation of this data set and during the preparation of this manuscript, we became aware that the nucleoside analogues or their components we had computed were reported in the chemical literature as products of model prebiotic syntheses (see, for example, refs and ) or laboratory syntheses concerned with other aspects of chemistry (see, for example, ref ). These studies underscore the utility of this approach and reinforce the notion that there may be many other nucleotide analogues remaining to be studied that could be prebiotically or biomedically relevant.…”

Section: Resultsmentioning

confidence: 99%

One Among Millions: The Chemical Space of Nucleic Acid-Like Molecules

Cleaves

Butch

Burger

et al. 2019

J. Chem. Inf. Model.

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Biology encodes hereditary information in DNA and RNA, which are finely tuned to their biological functions and modes of biological production. The central role of nucleic acids in biological information flow makes them key targets of pharmaceutical research. Indeed, other nucleic acid-like polymers can play similar roles to natural nucleic acids both in vivo and in vitro; yet despite remarkable advances over the last few decades, much remains unknown regarding which structures are compatible with molecular information storage. Chemical space describes the structures and properties of molecules that could exist within a given molecular formula or other classification system. Using structure generation methods, we explore nucleic acid analogues within the formula ranges BC 3−7 H 5−15 O 2−4 and BC 3−6 H 5−15 N 1−2 O 0−4 , where B is a recognition element (e.g., a nucleobase). Other restrictions included two obligatory points of attachment for inclusion into a linear polymer and substructures predicting chemical stability. These sets contain 86,007 (CHO) and 75,309 (CHNO) compositionally isomeric structures, representing 706,568 CHO and 454,422 CHNO stereoisomers, that diversely and densely occupy this space. These libraries point toward there being large spaces of unexplored chemistry relevant to pharmacology and biochemistry and efforts to understand the origins of life.

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“…As such, modified nucleosides mimicking their natural counterparts have a long history in medicinal and biological chemistry. − Today, modified nucleosides are indispensable pharmaceuticals for the treatment of various types of cancer and viral infections and further represent important tools in chemical biology for a spectrum of imaging applications. , Despite the great demand for these molecules, the synthesis of nucleosides is still regarded as challenging and inefficient . While nucleosides with ribosyl or 2′-deoxyribosyl moieties can be accessed from naturally occurring nucleosides or carbohydrates, − the preparation of sugar-modified nucleosides typically suffers from lengthy reaction sequences and low total yields. − Furthermore, a heavy reliance on protecting groups entails low overall efficiencies, and several sugar modifications at the 2′ or 4′ positions are known to limit diastereoselectivity in glycosylation approaches, , severely complicating the synthetic access to many target compounds. More importantly, established routes typically exhibit a lack of divergence as they tend to be specific to one nucleoside.…”

mentioning

confidence: 99%

Diversification of 4′-Methylated Nucleosides by Nucleoside Phosphorylases

et al. 2021

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The growing demand for 4′-modified nucleoside analogs in medicinal and biological chemistry is contrasted by the challenging synthetic access to these molecules and the lack of efficient diversification strategies. Herein, we report the development of a biocatalytic diversification approach based on nucleoside phosphorylases, which allows the straightforward installation of a variety of pyrimidine and purine nucleobases on a 4′-alkylated sugar scaffold. Following the identification of a suitable biocatalyst as well as its characterization with kinetic experiments and docking studies, we systematically explored the equilibrium thermodynamics of this reaction system to enable rational yield prediction in transglycosylation reactions via principles of thermodynamic control. Collectively, this work provides analytical methods and thermodynamic frameworks that outline a general roadmap for the characterization of nucleoside phosphorolysis and transglycosylation systems.

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Novel conformationally constrained 2′-C-methylribonucleosides: synthesis and incorporation into oligonucleotides

Cited by 9 publications

References 26 publications

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

One Among Millions: The Chemical Space of Nucleic Acid-Like Molecules

Diversification of 4′-Methylated Nucleosides by Nucleoside Phosphorylases

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