6-modified bicyclic nucleic acid analogs
View Patent ↗The present invention provides 6-modified bicyclic nucleoside analogs and oligomeric compounds comprising these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 6-position. These bicyclicnucleoside analogs are useful for enhancing properties of oligomeric compounds including nuclease resistance.
1. An oligomeric compound having at least one monomer of formula:
or of formula:
or of formula:
wherein independently for each of said at least one monomer of formula I, II or III:
Bx is a heterocyclic base moiety;
T 3 and T 4 are each, independently, an internucleoside linking group linking the monomer to the oligomeric compound or one of T 3 and T 4 is an internucleoside linking group linking the monomer to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group or a linked conjugate group;
Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thiol;
each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , OC(═X)J 1 , OC(═X)NJ 1 J 2 , NJ 3 C(═X)NJ 1 J 2 and CN, wherein each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl, and X is O, S or NJ 1 ;
wherein said oligomeric compound further comprises at least one monomeric subunit selected from a β-D-2′-deoxyribonucleoside, a β-D-ribonucleoside and a nucleoside having a modified sugar moiety wherein each of said modified sugar moieties is, independently, selected from a modified sugar moiety that is substituted with a substituent group, substituted at the 4′-O with a 4′-S, 4′-amino or C 1 -C 6 aminoalkyl, or bridged to form a bicyclic nucleic acid (BNA);
wherein said oligomeric compound comprises from 8 to 40 nucleosides and/or modified nucleosides or mimetics in length.
2. The oligomeric compound of claim 1 wherein each of said modified sugar moieties is, independently, selected from 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.
3. The oligomeric compound of claim 1 wherein each Z is, independently, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.
4. The oligomeric compound of claim 3 wherein each Z is methyl.
5. The oligomeric compound of claim 3 wherein each Z is substituted C 1 -C 6 alkyl.
6. The oligomeric compound of claim 5 wherein each of said substituent groups is C 1 -C 6 alkoxy.
7. The oligomeric compound of claim 6 wherein each Z is CH 3 OCH 2 —.
8. The oligomeric compound of claim 1 wherein the Z group of each monomer of said formula has the configuration represented by formula:
or the formula:
or the formula:
9. The oligomeric compound of claim 1 wherein the Z group of each monomer of said formula has the configuration represented by formula:
or the formula:
or the formula:
10. The oligomeric compound of claim 1 wherein each internucleoside linking group is selected from phosphodiester or phosphorothioate.
11. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate.
12. An oligomeric compound having the formula:
[T-L] j -[R-L] 1 -R-[L-T] r
wherein:
each T is a monomer of formula I:
wherein:
Bx is a heterocyclic base moiety;
Z is C 1 -C 6 alkyl, C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted C 2 -C 6 alkenyl, substituted C 2 -C 6 alkynyl, acyl, substituted acyl, substituted amide, thiol or substituted thiol;
each L is an internucleoside linking group;
each R is a β-D-2′-deoxyribonucleoside;
j is 0 or from 1 to about 3;
q is from 8 to about 14;
r is 0 or from 1 to about 3;
the sum of j and r is greater than 1;
the sum of j, q and r is from 7 to 39; and
each T and R located at a 5′ or 3′ terminus further comprises an optionally protected 5′ or 3′ hydroxyl group or a 5′ or 3′ linked conjugate group; and
wherein each of the substituted groups, is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, hydroxyl, OJ 1 , NJ 1 J 2 , SJ 1 , N 3 , OC(═X)J 1 , OC(═X)NJ 1 J 2 , NJ 3 C(═X)NJ 1 J 2 and CN, wherein each J 1 , J 2 and J 3 is, independently, H or C 1 -C 6 alkyl, and X is O, S or NJ 1 .
13. The oligomeric compound of claim 12 wherein each Z is, independently, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl.
14. The oligomeric compound of claim 13 wherein each Z is methyl.
15. The oligomeric compound of claim 13 wherein each Z is substituted C 1 -C 6 alkyl.
16. The oligomeric compound of claim 15 wherein each of said substituent groups is C 1 -C 6 alkoxy.
17. The oligomeric compound of claim 16 wherein each Z is CH 3 OCH 2 —.
18. The oligomeric compound of claim 12 wherein the Z group of each monomer of said formula has the configuration represented by formula:
or the formula:
or the formula:
19. The oligomeric compound of claim 12 wherein the Z group of each monomer of said formula has the configuration represented by formula:
or the formula:
or the formula:
20. The oligomeric compound of claim 12 wherein each internucleoside linking group is selected from phosphodiester or phosphorothioate.
21. The oligomeric compound of claim 12 wherein each internucleoside linking group is a phosphorothioate.
22. The oligomeric compound of claim 12 wherein j is 0.
23. The oligomeric compound of claim 12 wherein r is 0.
24. The oligomeric compound of claim 12 wherein j and r are each other than 0.