Oligonucleotides backbone modifications

In an oligonucleotide having n backbone linkages, this gives rise to 2 isomers that vary in their mechanism of action, cellular transport, as well as pharmacokinetics (53). Some of the most frequently encountered backbone modifications are Hsted in Table 1. 

Example 56 the Isis Pharmaceutical group in their extensive investigations of antisense oligonucleotides as therapeutics has described the synthesis of 3 -C-methylene nucleoside phosphonoamidites for the new backbone modification of oligonucleotides [90]. This paper gives good insight into tricoordinate phosphorus and related H-phosphonate chemistry in the service of nucleotide synthesis. 

The most straightforward modifications of natural oligonucleotide backbones are constitutional changes involving the 5 —3 phosphodiester linkage. Since 5 — -2 oligonucleotides are biologically known but not... 

Hybridon Inc. Backbone modification Synthesis of radioactively labeled oligonucleotides W09614277 1996... 

Emory University, USA Base, sugar, backbone modification Usage of carborane oligonucleotides in anticancer treatment WO9614073 1996... 

Amgen Inc. Backbone modification 5 -Dithiomodified oligonucleotides WO9604295 1996... 

Many types of chemically modified antisense ONs have been manufactured with the changes in the overall electronic charge as well as the incorporation of nonphosphate oligonucleotide backbones. They are commonly grouped into three generations based on the type of modifications (Figure 7.5-4). 

For RNA, artificial self-cleaving hammerhead ribozymes with a triazole linkage at the active site are reported [26]. Interestingly, triazole backbone modifications in RNA by CuAAC and SPAAC chemical hgation of 3 -azide and 5 -cyclooctyne oligonucleotides can further be reverse transcribed into DNA while one nucleotide is omitted at the linkage [95]. 

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