A ring-closing metathesis based synthesis of bicyclic nucleosides locked in S-type conformations by hydroxyl functionalised 3′,4′-trans linkages

Freitag, Morten; Thomasen, Helena; Christensen, Nanna K.; Petersen, Michael; Nielsen, P. H.

doi:10.1016/j.tet.2004.03.019

Cited by 28 publications

(12 citation statements)

References 45 publications

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“…Changing the configuration of the 5′-alkyl substituents in these analogs had a significant impact on RNA-affinity and immunostimulatory profiles of the PS ASOs ( 14 ). The second class of 5′-modified nucleic acids include modifications such as bicyclo- and tricyclo-DNA ( 15–17 ), α,β-CNA ( 18 , 19 ), backbone-constricted ( 20 , 21 ), and dual constrained analogs of LNA ( 22 ) and α-L-LNA ( 23 ) that show significant increases in RNA-affinity and interesting biological properties ( 24 , 25 ). In these analogs, the 5′-substitutent is covalently tethered to restrict rotation around multiple backbone torsion angles depending on the mode of constraint employed.…”

Section: Introductionmentioning

confidence: 99%

Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

Vasquez

Freestone

Wan

et al. 2021

Nucleic Acids Research

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We recently showed that site-specific incorporation of 2′-modifications or neutral linkages in the oligo-deoxynucleotide gap region of toxic phosphorothioate (PS) gapmer ASOs can enhance therapeutic index and safety. In this manuscript, we determined if introducing substitution at the 5′-position of deoxynucleotide monomers in the gap can also enhance therapeutic index. Introducing R- or S-configured 5′-Me DNA at positions 3 and 4 in the oligodeoxynucleotide gap enhanced the therapeutic profile of the modified ASOs suggesting a different positional preference as compared to the 2′-OMe gap modification strategy. The generality of these observations was demonstrated by evaluating R-5′-Me and R-5′-Ethyl DNA modifications in multiple ASOs targeting HDAC2, FXI and Dynamin2 mRNA in the liver. The current work adds to a growing body of evidence that small structural changes can modulate the therapeutic properties of PS ASOs and ushers a new era of chemical optimization with a focus on enhancing the therapeutic profile as opposed to nuclease stability, RNA-affinity and pharmacokinetic properties. The 5′-methyl DNA modified ASOs exhibited excellent safety and antisense activity in mice highlighting the therapeutic potential of this class of nucleic acid analogs for next generation ASO designs.

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Section: Introductionmentioning

confidence: 99%

Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

Vasquez

Freestone

Wan

et al. 2021

Nucleic Acids Research

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“…Unlike the synthetic route to 12 (Scheme ), where the carbocyclic ring was formed before the thymine nucleobase was introduced, it was critical to reverse these synthetic operations in the synthesis of analogue 13 . Others have reported unwanted side reactions to occur when related trans -1-oxabicyclo[4.3.0]nonane systems have been subjected to acidic hydrolysis of a C 1 ,C 2 -isopropylidene group, and a similar result was observed with the C 3 /C 5 -epimer of 28 . Therefore, treatment of 35 with DOWEX 50W8X, acetylation of the resulting mixture of diastereomeric diols, and application of the Vorbrüggen reaction furnished 37 in 81% yield over three steps.…”

Section: Results and Discussionmentioning

confidence: 82%

“…After 18 h, the reaction mixture was diluted with dichloromethane (50 mL) and the resulting solution was washed with water (100 mL), a saturated solution of NaHCO 3 (100 mL), and brine (100 mL), dried over MgSO 4 , filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography (17 × 1.5 cm; 4/1 EtOAc/hexanes) to give 31 as a colorless foam (0.224 g, 92%): R f = 0.23 (4/1 EtOAc/hexanes); [α] D 20 −37 (c 0.17, CHCl 3 ); 1 1-((2R,3aR,7S,7aS)-7-(Benzyloxy)-3a-hydroxyoctahydrobenzofuran-2-yl)-5-methylpyrimidine-2,4(1H,3H)-dione (32). Tributyltin hydride (0.231 g, 0.792 mmol) and AIBN (0.002 mg, 0.01 mmol), as a solution in toluene (2 mL), were added to a stirred a 110 °C of 31 (0.066 g, 0.132 mmol) in toluene (10 mL).…”

Section: ■ Conclusionmentioning

confidence: 99%

Synthesis of cis- and trans-α-l-[4.3.0]Bicyclo-DNA Monomers for Antisense Technology: Methods for the Diastereoselective Formation of Bicyclic Nucleosides

et al. 2013

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Two α-L-ribo-configured bicyclic nucleic acid modifications, represented by analogues 12 and 13, which are epimeric at C3' and C5' have been synthesized using a carbohydrate-based approach to build the bicyclic core structure. An intramolecular L-proline-mediated aldol reaction was employed to generate the cis-configured ring junction of analogue 12 and represents a rare application of this venerable organocatalytic reaction to a carbohydrate system. In the case of analogue 13, where a trans-ring junction was desired, an intermolecular diastereoselective Grignard reaction followed by ring-closing metathesis was used. In order to set the desired stereochemistry at the C5' positions of both nucleoside targets, a study of diastereoselective Lewis acid mediated allylation reactions on a common bicyclic aldehyde precursor was carried out. Analogue 12 was incorporated in oligonucleotide sequences, and thermal denaturation experiments indicate that it is destabilizing when paired with complementary DNA and RNA. However, this construct shows a significant improvement in nuclease stability relative to a DNA oligonucleotide.

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“…As mentioned above, we planned to introduce the additional 2‘,4‘-bridge into the desired nucleosides via a ring-closing metathesis (RCM) reaction. This type of reaction has been successfully used on nucleoside and nucleotide substrates by us , and others for making varying sizes of rings, including a bicyclic nucleoside with a conformationally restricting 3‘,4‘-linkage . The RCM transformation leading to our target nucleosides 8 and 9 requires a 2‘-deoxynucleoside substrate with a vinyl group in the 4‘-C position and an allyl group in the 2‘-C position.…”

Section: Resultsmentioning

confidence: 99%

Analogues of a Locked Nucleic Acid with Three-Carbon 2‘,4‘-Linkages: Synthesis by Ring-Closing Metathesis and Influence on Nucleic Acid Duplex Stability and Structure

2006

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Two bicyclic 2'-deoxynucleoside analogues containing a saturated and an unsaturated three-carbon 2',4'-linkage, respectively, have been synthesized using a ring-closing metathesis-based linear strategy starting from uridine. Both analogues have been incorporated into oligodeoxynucleotide sequences and increased the stability of DNA:RNA hybrid duplexes (DeltaT(m) approximately 2.5-5.0 degrees C per modification) and decreased the stability of dsDNA duplexes (DeltaT(m) approximately 2.5-1.0 degrees C per modification). CD spectroscopy revealed that the bicyclic nucleosides induced formation of A-type-like duplexes albeit to a lesser degree than found for locked nucleic acid (LNA) monomers. From the CD data and UV melting analysis, we propose that the 2'-oxygen atom of the bicyclic moiety is essential for the formation of stabilized A-type-like dsDNA but not for the formation of a stabilized A-type DNA:RNA hybrid.

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A ring-closing metathesis based synthesis of bicyclic nucleosides locked in S-type conformations by hydroxyl functionalised 3′,4′-trans linkages

Cited by 28 publications

References 45 publications

Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

Site-specific incorporation of 5′-methyl DNA enhances the therapeutic profile of gapmer ASOs

Synthesis of cis- and trans-α-l-[4.3.0]Bicyclo-DNA Monomers for Antisense Technology: Methods for the Diastereoselective Formation of Bicyclic Nucleosides

Analogues of a Locked Nucleic Acid with Three-Carbon 2‘,4‘-Linkages: Synthesis by Ring-Closing Metathesis and Influence on Nucleic Acid Duplex Stability and Structure

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