Synthesis and restricted furanose conformations of three novel bicyclic thymine nucleosides: a xylo-LNA nucleoside, a 3′-O,5′-C-methylene-linked nucleoside, and a 2′-O,5′-C-methylene-linked nucleoside

Rajwanshi, Vivek K.; Kumar, Ravindra; Kofod-Hansen, Mikael; Wengel, Jesper

doi:10.1039/a901729a

Cited by 26 publications

(25 citation statements)

References 24 publications

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“…[32], 2 steps, 62 %; c) i) (COCl) 2 , DMSO, Et 3 N, CH 2 Cl 2 ; ii) CH 2 O, NaOH, H 2 O, THF, 63 % from 12; d) ref. [29], 3 steps on enantiomers, 82 %; e) refs. [27,29], 5 steps on enantiomers, 40 %.…”

Section: Resultsmentioning

confidence: 99%

“…[29], 3 steps on enantiomers, 82 %; e) refs. [27,29], 5 steps on enantiomers, 40 %. synthesised [27] by using diacetone-d-glucose as the starting material, which was converted to the 3'-epimer of 4 (the enantiomer of 13; Scheme 4) [28] as an intermediate product.…”

Section: Resultsmentioning

confidence: 99%

“…synthesised [27] by using diacetone-d-glucose as the starting material, which was converted to the 3'-epimer of 4 (the enantiomer of 13; Scheme 4) [28] as an intermediate product. [27,29] Therefore, 2 should be accessible from 13, suggesting the use of another carbohydrate precursor that may be converted to 13. As the only reasonably cheap starting material with this potential, d-arabinose was chosen.…”

Section: Resultsmentioning

confidence: 99%

“…[32] Subsequently, the primary alcohol function of 12 was oxidised using the Swern protocol to give an aldehyde and, after the usual aldol condensation and Cannizzarro reaction, 13 was obtained in good yield. We have not employed this material in the synthesis of 2, but as 13, by comparison of its NMR data, was shown to be the enantiomer of a known compound, [28] and as that compound has been used in the stereoselective eight-step synthesis of the a-l-LNA thymine monomer, [27,29] that is, through stereoselective coupling of thymine to the enantiomers of 13 a and without the application of any chiral reagents, we concluded that this strategy could afford 2 in the same overall yield. However, and despite the lack of stereoselectivity, the original method (Scheme 2) is still considered as superior due to the fact that it requires fewer reaction steps and the key intermediate 4 [23] is more readily available compared to its stereoisomer 13.…”

Section: Resultsmentioning

confidence: 99%

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α-LNA (Locked Nucleic Acid withα-D-Configuration): Synthesis and Selective Parallel Recognition of RNA

2002

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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α-LNA (Locked Nucleic Acid withα-D-Configuration): Synthesis and Selective Parallel Recognition of RNA

2002

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“…(3,4) Based on these findings, our laboratory (5–7) and others (8–11) have focused on the synthesis of novel nucleoside analogs that are biased toward one specific ring pucker as potential therapeutic agents. The concept of ‘locking’(12) the furanose ring pucker by various synthetic manipulations began about 13 years ago and gave rise to a range of different analogs (7,10,13,14). Notable examples in the field derive from the bridged nucleic acids (BNAs) concept (8), where analogs contain an added ring that bridges two atoms of the furanose.…”

Section: Introductionmentioning

confidence: 99%

Biophysical studies of DNA modified with conformationally constrained nucleotides: comparison of 2'-exo (north) and 3'-exo (south) 'locked' templates

Maderia

Shenoy

Van

et al. 2007

Nucleic Acids Research

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The biophysical properties of oligodeoxyribonucleotides (ODNs) selectively modified with conformationally ‘locked’ bicyclo[3.1.0]hexane pseudosugars (Maier,M.A., Choi,Y., Gaus,H., Barchi,J.J. Jr, Marquez,V.E., Manoharan,M. (2004) Synthesis and characterization of oligonucleotides containing conformationally constrained bicyclo[3.1.0]hexane pseudosugar analogs Nucleic Acids Res., 32, 3642–3650) have been studied by various techniques. Six separate synthetic ODNs based on the Dickerson Drew dodecamer sequence (CGCGAAT*T*CGCG) were examined where each one (or both) of the thymidines (T*) were substituted with a bicyclic pseudosugar locked in either a North (2′-exo) or South (3′-exo) ring pucker. Circular dichroism spectroscopy, differential scanning calorimetry and 1H NMR spectroscopy were used to examine the duplex stability and conformational properties of the ODNs. Replacement of one or both thymidines with North-locked sugars (RNA-like) into the dodecamer did not greatly affect duplex formation or melt temperatures but distinct differences in thermodynamic parameters were observed. In contrast, incorporation of South-locked sugar derivatives that were predicted to stabilize this standard B-DNA, had the unexpected effect of causing a conformational equilibrium between different duplex forms at specific strand and salt concentrations. Our data and those of others suggest that although DNA can tolerate modifications with RNA-like (North) nucleotides, a more complicated spectrum of changes emerges with modifications restricted to South (DNA-like) puckers.

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On the in vitro and in vivo Properties of Four Locked Nucleic Acid Nucleotides Incorporated into an Anti‐H‐Ras Antisense Oligonucleotide

Fluiter

Frieden²,

Vreijling

et al. 2005

ChemBioChem

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Locked nucleic acid (beta-D-LNA) monomers are conformationally restricted nucleotides bearing a methylene 2'-O, 4'-C linkage that have an unprecedented high affinity for matching DNA or RNA. In this study, we compared the in vitro and in vivo properties of four different LNAs, beta-D-amino LNA (amino-LNA), beta-D-thio LNA (thio-LNA), beta-D-LNA (LNA), and its stereoisomer alpha-L-LNA in an antisense oligonucleotide (ODN). A well-known antisense ODN design against H-Ras was modified at the 5'- and 3'-ends with the different LNA analogues (LNA-DNA-LNA gapmer design). The resulting gapmers were tested in cancer-cell cultures and in a nude-mouse model bearing prostate tumor xenografts. The efficacy in target knockdown, the biodistribution, and the ability to inhibit tumor growth were measured. All anti H-Ras ODNs were very efficient in H-Ras mRNA knockdown in vitro, reaching maximum effect at concentrations below 5 nM. Moreover, the anti-H-Ras ODN containing alpha-L-LNA had clearly the highest efficacy in H-Ras knockdown. All LNA types displayed a great stability in serum. ODNs containing amino-LNA showed an increased uptake by heart, liver, and lungs as compared to the other LNA types. Both alpha-L-LNA and LNA gapmer ODNs had a high efficacy of tumor-growth inhibition and were nontoxic at the tested dosages. Remarkably, in vivo tumor-growth inhibition could be observed at dosages as low as 0.5 mg kg(-1) per day. These results indicate that alpha-L-LNA is a very promising member of the family of LNA analogues in antisense applications.

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Synthesis and restricted furanose conformations of three novel bicyclic thymine nucleosides: a xylo-LNA nucleoside, a 3′-O,5′-C-methylene-linked nucleoside, and a 2′-O,5′-C-methylene-linked nucleoside

Cited by 26 publications

References 24 publications

α-LNA (Locked Nucleic Acid withα-D-Configuration): Synthesis and Selective Parallel Recognition of RNA

α-LNA (Locked Nucleic Acid withα-D-Configuration): Synthesis and Selective Parallel Recognition of RNA

Biophysical studies of DNA modified with conformationally constrained nucleotides: comparison of 2'-exo (north) and 3'-exo (south) 'locked' templates

On the in vitro and in vivo Properties of Four Locked Nucleic Acid Nucleotides Incorporated into an Anti‐H‐Ras Antisense Oligonucleotide

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