Oligonucleotide analogues and methods utilizing the same
A method for the prevention or treatment in a mammal of a disease preventable or treatable by the pharmacologically useful antisense or antigene activity of an oligonucleotide analogue or a pharmacologically acceptable salt thereof in the body of said mammal, which method comprises administering to said mammal in need of such prevention or treatment a pharmaceutically effective amount of an oligonucleotide analogue comprising two or more nucleoside units, wherein at least one of said nucleoside units is a structure of the formula (2): wherein A is methylene; and B is an unsubstituted purin-9-yl, an unsubstituted 2-oxo-pyrimidin-1-yl or a substituted purin-9-yl; or a pharmacologically acceptable salt thereof.
1. An antigene oligonucleotide comprising two or more nucleoside units, wherein at least one of said nucleoside units has a structure of formula (2):
said nucleoside units being bonded through a phosphodiester bond or a phosphorothioate bond, wherein:
A represents a methylene group; and
B is a group selected from the group consisting of 6-benzoylaminopurin-9-yl, adeninyl, 2-isobutyrylamino-6-hydroxypurin-9-yl, guaninyl, 2-oxo-4-benzoylamino-pyrimidin-1-yl, cytosinyl, 2-oxo-5-methyl-4-benzoylamino-pyrimidin-1-yl, 5-methylcytosinyl, uracinyl and thyminyl groups.
2. The antigene oligonucleotide according to claim 1 , wherein the oligonucleotide analogue, B is an adeninyl group.
3. The antigene oligonucleotide according to claim 1 , wherein the oligonucleotide analogue, B is a guaninyl group.
4. The antigene oligonucleotide according to claim 1 , wherein the oligonucleotide analogue, B is a uracinyl group.
5. The antigene oligonucleotide according to claim 1 , wherein the oligonucleotide analogue, B is a cytosinyl group.
6. The antigene oligonucleotide according to claim 1 , wherein the oligonucleotide analogue, B is a 5-methylcytosinyl group.
7. A nucleoside analog represented by the following structural formula:
wherein B is adenine, guanine, thymine, 5-methyl-cytosine, cytosine, or uracil.
8. The nucleoside analogue of claim 7 , wherein the analogue is one of the following specific compounds:
a) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(adenin-9-yl)-2,6-dioxabicyclo[3.2.1]octane,
b) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(guanin-9-yl)-2,6-dioxabicyclo[3.2.1]octane,
c) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(thymin-1-yl)-2,6-dioxabicyclo[3.2.1]octane,
d) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(5-methyl-cytosin-1-yl)-2,6-dioxabicyclo[3.2.1]octane,
e) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(cytosin-1-yl)-2,6-dioxabicyclo[3.2.1]octane, and
f) (1R,5R,7R,8S)-8-hydroxy-5-(hydroxymethyl)-7-(uracil-1-yl)-2,6-dioxabicyclo[3.2.1]octane.
9. A compound selected from the group consisting of
2′-O,4′-C-ethyleneguanosine,
2′-O,4′-C-ethyleneadenosine,
2′-O,4′-C-ethyleneuridine,
2′-O,4′-C-ethylene-5-methyluridine,
2′-O,4′-C-ethylenecytidine, and
2′-O,4′-C-ethylene-5-methylcytidine.
10. A compound selected from the group consisting of
2′-O,4′-C-ethyleneguanosine,
2′-O,4′-C-ethyleneadenosine,
3′,5′-di-O-benzyl-2-O,4′-C-ethylene-6-N-benzoyladenosine,
3′,5′-di-O-benzyl-2-O,4′-C-ethylene-2-N-isobutyrylguanosine,
5′-O-dimethoxytrityl-2-O,4′-C-ethylene-6-N-benzoyladenosine,
5′-O-dimethoxytrityl-2-O,4′-C-ethylene-2-N-isobutyrylguanosine,
2′-O,4′-C-ethylene-2-N-isobutyrylguanosine,
2′-O,4′-C-ethylene-6-N-benzoyladenosine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-6-N-benzoyladenosine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-2-N-isobutyrylguanosine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite,
2′-O,4′-C-ethyleneuridine,
2′-O,4′-C-ethylene-5-methyluridine,
2′-O,4′-C-ethylenecytidine,
2′-O,4′-C-ethylene-5-methylcytidine,
3′,5′-di-O-benzyl-2′-O,4′-C-ethyleneuridine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethyleneuridine,
3′,5′-di-O-benzyl-2′-O,4′-C-ethylene-5-methyluridine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-5-methyluridine,
3′,5′-di-O-benzyl-2′-O,4′-C-ethylene-4-N-benzoylcytidine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoylcytidine,
3′,5′-di-O-benzyl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcytidine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcytidine,
2′-O,4′-C-ethylene-4-N-benzoylcytidine,
2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcytidine,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-uridine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-5-methyluridine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite,
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoylcytidine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite, and
5′-O-dimethoxytrityl-2′-O,4′-C-ethylene-4-N-benzoyl-5-methylcytidine-3′-O-(2-cyanoethyl N,N-diisopropyl)phosphoramidite.
11. An oligonucleotide analogue comprising two or more nucleoside units wherein at least one of said nucleoside units is a structure of the formula:
wherein:
B is selected from the group consisting of adenine, guanine, thymine, 5-methyl-cytosine, cytosine, and uracil.
12. An oligonucleotide analogue comprising two or more nucleoside units wherein at least one of said nucleoside units is a structure of the formula:
wherein:
A represents a methylene group; and
B is selected from the group consisting 6-benzoylaminopurin-9-yl, adeninyl, 2-isobutyrylamino-6-hydroxypurin-9-yl, guaninyl, 2-oxo-4-benzoylamino-pyrimidin-1-yl, cytosinyl, 5-methylcytosinyl, uracinyl and thyminyl groups.
13. An oligonucleotide analogue comprising two or more nucleoside units wherein at least one of said nucleoside units is a structure of the formula:
wherein:
A represents a methylene group; and
B is 2-oxo-5-methyl-4-benzoylamino- pyrimidin-1-yl.