New light labile linker for solid phase synthesis of 2′- O-acetalester oligonucleotides and applications to siRNA prodrug development

A novel light labile linker for RNA synthesis was developed and used in the synthesis of acetalester conjugates. We report on the synthesis and properties of oligonucleotides containing 2′- O-(levulinic acid) and 2′- O-(amino acid) acetalesters. Given that esters serve as promoieties in several ther...

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Veröffentlicht in:Bioorganic & medicinal chemistry letters 2011-06, Vol.21 (12), p.3721-3725
Hauptverfasser: Johnsson, Richard, Lackey, Jeremy G., Bogojeski, Jovanka J., Damha, Masad J.
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Sprache:eng
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Zusammenfassung:A novel light labile linker for RNA synthesis was developed and used in the synthesis of acetalester conjugates. We report on the synthesis and properties of oligonucleotides containing 2′- O-(levulinic acid) and 2′- O-(amino acid) acetalesters. Given that esters serve as promoieties in several therapeutic prodrugs, we believe that these derivatives will have potential use as nucleic acid prodrugs. In addition, we report on the synthesis of a novel solid support with a photolabile linker that not only allows for the synthesis of oligonucleotides containing various 2′- O-acetalesters, but can be generally adopted to the synthesis of base-sensitive oligoribonucleotides. The release of oligonucleotides from this support is faster than with conventional linkers.
ISSN:0960-894X
1464-3405
DOI:10.1016/j.bmcl.2011.04.073