Synthetic Nucleosides and Nucleotides. 37. Antisense Oligodeoxynucleotides Bearing 5-(Phenylethyl)-2′-deoxyuridylate at the 3′-Terminus: Exonuclease-Resistant Molecule with Natural Phosphodiester Backbone

Abstract

5-(Phenylethyl)-2'-deoxyuridine has been incorporated into an oligodeoxynucleotide (ODN) by using normal cyanoethyl phosphoramidite chemistry on a DNA synthesizer. For introduction of the modified residue at the 3'-end position of the ODN, we designed and synthesized a new nucleoside phosphoramidite derivative, which connected the 3'-hydroxyl group and phosphoramidite moiety by an alkaline-labile linker. The 3'-end could be substituted in ODNs by using commercially available supports as a starting material following standard NH4OH treatment. The ODN carrying 5-(phenylethyl)-2'-deoxyuridine at the 3'-end position showed about 3-fold resistance to nucleolytic degradation in human plasma without precluding its specific base-pairing activity.

Liposomal Delivery of a 30-mer Antisense Oligodeoxynucleotide To Inhibit Proopiomelanocortin Expression†

“…3,21 Other chemical modifications involved the heterocyclic bases. 22,23 The other important parameter to be fulfilled is the intracellular uptake considering that drug therapy relies principally on the drug's ability to access the biological target. Therefore, this theoretical concern is critical in the successful application of antisense technology.…”