5′-modified bicyclic nucleic acid analogs
View Patent ↗The present invention provides 5′-modified bicyclic nucleoside analogs and oligomeric compounds comprising at least one of these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 5′-carbon. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including for example enhanced nuclease resistance.
1. An oligomeric compound having Formula II:
G-[T-L] j -[R-L] q -R-[L-T] r -E II
wherein:
each R is a β-D-2′-deoxyribonucleoside;
each L is, independently, a phosphodiester or phosphorothioate internucleoside linking group;
each T is a monomer of Formula III:
wherein independently for each monomer having Formula III:
Bx is a heterocyclic base moiety;
Z is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with C 2 -C 6 alkenyl, C 1 -C 6 alkoxy or one or more fluoro atoms;
G and E are each, independently, H, a hydroxyl protecting group or a linked conjugate group;
q is from 7 to about 15;
j is 0 or from 1 to about 5;
r is 0 or from 1 to about 5; and
the sum of j and r is at least 1.
2. The oligomeric compound of claim 1 wherein each Z is a substituted C 1 -C 6 alkyl.
3. The oligomeric compound of claim 2 wherein each Z is substituted methyl.
4. The oligomeric compound of claim 1 wherein each Z is methyl, ethyl or methoxymethylene.
5. The oligomeric compound of claim 4 wherein each Z is methyl.
6. The oligomeric compound of claim 1 wherein each Z is vinyl.
7. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.
8. The oligomeric compound of claim 1 wherein j is 0.
9. The oligomeric compound of claim 1 wherein r is 0.
10. The oligomeric compound of claim 1 wherein j and r are each other than 0.
11. The oligomeric compound of claim 1 wherein j and r are each 2.
12. The oligomeric compound of claim 11 wherein q is from about 9 to about 13.
13. The oligomeric compound of claim 12 wherein q is 10.
14. The oligomeric compound of claim 1 wherein j and r are each 5.
15. The oligomeric compound of claim 14 wherein q is about 10.
16. An oligomeric compound comprising at least one monomer having Formula IV:
wherein independently for each monomer having Formula IV:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is an internucleoside linking group attaching the monomer having Formula IV to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside linking group attaching the monomer having Formula IV to the oligomeric compound;
Z is C 1 -C 6 alkyl or C 1 -C 6 alkyl substituted with C 2 -C 6 alkenyl, C 1 -C 6 alkoxy or one or more fluoro atoms;
said oligomeric compound comprising at least one monomeric subunit that is other than a monomer having formula IV, selected from a β-D-ribonucleoside, a β-D-2′-deoxyribonucleoside and a modified nucleoside wherein said modified nucleoside comprises at least a sugar substituent group, a 4′-S group or a bicyclic modified sugar; and
wherein said oligomeric compound comprises from 8 to 40 nucleosides and/or modified nucleosides or mimetics in length.
17. The oligomeric compound of claim 16 wherein each Z is a substituted C 1 -C 6 alkyl for each monomer having Formula IV.
18. The oligomeric compound of claim 16 wherein each Z is a substituted methyl for each monomer having Formula IV.
19. The oligomeric compound of claim 16 wherein each Z is methyl, ethyl or methoxymethylene for each monomer having Formula IV.
20. The oligomeric compound of claim 16 wherein each Z is a methyl for each monomer having Formula IV.
21. The oligomeric compound of claim 16 wherein each Z is vinyl for each monomer having Formula IV.
22. The oligomeric compound of claim 16 wherein each of said modified nucleosides comprises at least a 2′-F modified sugar moiety, a 2′-OCH 3 modified sugar moiety, a 2′-O—(CH 2 ) 2 —OCH 3 modified sugar moiety, a 2′-O—CH 2 -4′ bicyclic modified sugar moiety or a 4′-S modified sugar moiety.
23. The oligomeric compound of claim 16 wherein one T 3 is H, a hydroxyl protecting group or a linked conjugate group.
24. The oligomeric compound of claim 16 wherein one T 4 is H, a hydroxyl protecting group or a linked conjugate group.
25. The oligomeric compound of claim 16 wherein each internucleoside linking group is, independently, a phosphodiester or phosphorothioate internucleoside linking group.
26. The oligomeric compound of claim 16 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.