Modifications for antisense compounds

1. An antisense oligonucleotide comprising at least one modification that is incorporated between two bases of the antisense oligonucleotide, wherein the modification increases binding affinity and nuclease resistance of the antisense oligonucleotide, and wherein the modification has the structure:

wherein

X is a nitrogen or carbon atom, wherein if X is a carbon atom, the fourth substituent attached to the carbon atom can be hydrogen or a C1-C8 alkyl group;

the linking groups L 1 and L 2 positioning the modification at an internal position of the oligonucleotide are independently alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, or alkoxy; and

R 1 -R 5 are independently hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, an electron withdrawing group, an electron donating group, an attachment point for a ligand, or

wherein

R 6 , R 7 , R 9 -R 12 are independently hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, an electron withdrawing group, or an electron donating group; and

R 8 is hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, or an electron withdrawing group.

2. The antisense oligonucleotide of claim 1 , wherein the modification is located within three bases of a terminal nucleotide.

3. The antisense oligonucleotide of claim 1 , wherein the modification is located between a terminal base and a penultimate base of either the 3′ or the 5′ end of the antisense oligonucleotide.

4. The antisense oligonucleotide of claim 1 , wherein the modification is located between the terminal base and the penultimate base at both the 3′ and the 5′ ends of the antisense oligonucleotide.

5. The antisense oligonucleotide of claim 1 , wherein the modification is a napthylene-azo compound.

6. The antisense oligonucleotide of claim 1 , wherein the modification has the structure:

wherein

the linking groups L 1 and L 2 positioning the modification at an internal position of the oligonucleotide are independently alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, or alkoxy;

R 1 , R 2 , R 4 , R 5 are independently hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, an electron withdrawing group, or an electron donating group;

R 6 , R 7 , R 9 -R 12 are independently hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, an electron withdrawing group, or an electron donating group;

R 8 is hydrogen, alkyl, alkynyl, alkenyl, heteroalkyl, substituted alkyl, aryl, heteroaryl, substituted aryl, cycloalkyl, alkylaryl, alkoxy, or an electron withdrawing group; and

X is a nitrogen or carbon atom, wherein if X is a carbon atom, the fourth substituent attached to the carbon atom can be hydrogen or a C1-C8 alkyl group.

7. The antisense oligonucleotide of claim 6 , wherein R 8 is an electron withdrawing group, which is NO 2 .

8. The antisense oligonucleotide of claim 1 , wherein the modification has the structure:

9. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide further comprises at least one 2′-O-methyl RNA.

10. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide further comprises one or more phosphorothioate linkages.

11. The antisense oligonucleotide of claim 1 , wherein the antisense oligonucleotide comprises a region of bases linked through phosphodiester bonds, wherein the region is flanked at one or both ends by regions containing phosphorothioate linkages.

12. An antisense oligonucleotide having the structure:

5′-X 1 —Z—X 2 —X 3 —X 4 —Z—X 5 -3′

wherein:

X 1 and X 5 are independently 1-3 nucleotides;

the internucleotide linkages are optionally phosphorothioate;

Z is a napthylene-azo compound;

X 2 and X 4 are independently 1-5 nucleotides wherein the internucleotide linkages are optionally phosphorothioate; and

X 3 is 10-25 nucleotides.