Bridged nucleic acids

Fig. 1 Modified nucleic acids with enhanced nuclease stability, a DNA, b phosphorothioate, c Z -OjT-C-methylene-bridged (locked) nucleic acid (LNA), d 2f-0,A -C-ethylene-bridged nucleic acid (ENA), e Z -O-methyl nucleic acid, f methylphosphonate-linked nucleic acid, g morpholino-linked nucleic acid, h peptide nucleic acid (PNA)...

The binding properties of 2 -0,-4 -C-ethylene bridged nucleic acids (ENA) (65) have been examined and compared with LNA. NMR demonstrated that ENA adopts the iV-conformation, as does LNA. In hybridisation studies, ENA showed an enhanced affinity towards RNA, but was slightly less stable than the corresponding LNA analogues. However, it was reported that ENA exhibits superior nuclease resistance to LNA. The bicyclic uridine nucleoside (15,5S,6S)-6-hydroxy-5-hydroxymethyl-l-(uracil-l-yl)-3,8-dioxabicyclo[3.2.1]octane (66) has been incorporated into ODNs where it was expected to restrict the sugar moiety into an OA -endo conformation. It was found that the presence of the analogue caused some destabilisation in duplexes with either DNA or RNA, thus a locked nucleic acid does not always lead to duplex stability. 

A number of other locked nucleosides have been studied, and Imanishi and Obika have reviewed a series of bridged nucleic acid analogues.2 -D,4 -C-ethylene (53) and propylene analogues also have C3 -endo conformations and... 

Morita K, Hasegawa C, Kanekoa M, et al. (2002) 2 -0,4 -C-ethylene-bridged nucleic acids (ENA) Highly nuclease-resistant and thermodynamically stable oligonucleotides for antisense drug. Bioorganic Medicinal Chemistry Letters 12 73-76. 

Bridged nucleic acids, or 2,4 -BNAs, are structurally the same as d-LNA, but research on BNAs has focused on triplex formation with ds-DNA.587 588 As observed with d-LNA, 2 -4 -BNA-C and -T incorpo-... 

Development of bridged nucleic acid analogs for antigene technology 04CPB1399. 

FIGURE 4.1 Chemical modifications to ribose sugar or phosphate linkages. BNA, bridged nucleic acid LNA, locked nucleic acid PMO, phosphorodiamidate morpholino oligomer. 

Imanishi has reported the synthesis and properties of a bridged nucleic acid analogue which contained a N3 P5 phosphoramidate linkage. " The heterodimer containing 3 -amino-2, 4 -BNA thymine monomer and thymine and methylcytosine monomers of 3 -amino-2, 4 -BNA and their 5 -phosphoramidites [34a-c] were synthesised from the intermediate 3 -azido 3 -deoxy-2, 4 -bicyclic thymidine. 

A novel class of 2 modified ohgonucleotides called locked nucleic acids (LNAs) has recently received attention. These are also referred to as bridged nucleic acids (BNAs) as the modification locks the furanose... 

Torigoe, H. et al, 2Co,4 -C-methylene bridged nucleic acid modification promotes pyrimidine motif triplex DNA formation at physiological pH thermodynamic and kinetic studies, /. Biol. Chem., 276, 2354, 2001. 

Abdur Rahman SM, Sato H, Tsuda N et al (2010) RNA interference with 2, 4 -bridged nucleic acid analogues. Bioorg Med Chem 18 3474—3480... 

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