Poly-substituted-phenyl-oligoribo nucleotides having enhanced stability and membrane permeability and methods of use

An antisense oligoribonucleotide derivatized at a plurality of 2'-O positions with a hydrophobic group selected from the group consisting of a 2,4-dinitrophenyl group and a 3-fluoro-4,6-dinitrophenyl group.

A method of enhancing membrane permeability and stability of an oligoribonucleotide, comprising:

• providing an oligoribonucleotide having a plurality of 2'-O positions;
• conjugating a substituted phenyl group at said plurality of 2'-O ribose positions to produce a derivatized compound of the following general structure:
• ##STR21## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently H, NO.sub.2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphorothioate, or phosphorothioate.

In an antisense therapeutic method, comprising administering an antisense oligonucleotide comprising a plurality of 2'-O positions in a manner designed inhibit gene expression, the improvement comprising:

• derivatizing the antisense oligonucleotide at a plurality of the 2'-O positions with a substituted phenyl group to produce a derivatized compound of the following structure:
• ##STR24## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently H, NO.sub.2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphorothioate.

In a method for administering an oligoribonucleotide, wherein the oligoribonucleotide comprises a plurality of 2'-O positions in a manner designed to inhibit gene expression the improvement comprising:

• derivatizing the O at a plurality of the 2'-O positions with a moiety selected from the group consisting of a 2,4-dinitrophenyl moiety and a 3-fluoro-4,6-dinitrophenyl moiety.

A method of derivatizing an oligoribonucleotide, comprising:

• providing an oligoribonucleotide having a plurality of 2'-O positions;
• conjugating a substituted phenyl group at a plurality of 2'-O positions to produce a derivatized compound of the following general structure:
• ##STR28## wherein R.sup.1, R.sup.2, R.sup.3, R.sup.4, and R.sup.5 are independently H, NO.sub.2, halide, linear or branched alkyl, linear or branched acyl, linear or branched alkylene, linear or branched O-alkyl, linear or branched amido, linear or branched S-alkyl, mono or disubstituted amine, linear or branched thioamido, phosphothionate, or phosphorothioate.

A method of derivatizing an oligoribonucleotide, comprising:

• providing an oligoribonucleotide having a plurality of 2'-O positions;
• reacting said oligoribonucleotide with a Sanger-type reagent at a plurality of 2'-O positions to produce a derivatized oligoribonucleotide of the following general structure:
• ##STR29##