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 the formula:
G-[T a -L] j -[R-L] q -R-[L-T b ] r -E
wherein:
each T a or each T b is a monomer of formula II:
wherein independently for each monomer of formula II:
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 or substituted acyl;
the other of each T a or each T b is a modified nucleoside wherein each modified nucleoside independently comprises 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;
each R is a β-D-2′-deoxyribonucleoside;
each L is an internucleoside linking group;
G and E are each, independently, H, a hydroxyl protecting group or a linked conjugate group;
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, OJ 1 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)—NJ 1 J 2 , N(H)C(═NH)NR 1 R 2 or N(H)C(═X)N(H)J 2 wherein X is O or S;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, substituted C 1 -C 6 alkyl, C 2 -C 6 alkenyl, substituted C 2 -C 6 alkenyl, C 2 -C 6 alkynyl, substituted C 2 -C 6 alkynyl, C 1 -C 6 aminoalkyl, substituted C 1 -C 6 aminoalkyl or a protecting group;
q is from 7 to about 15;
j is from 1 to about 5; and
r is from 1 to about 5.
2. The oligomeric compound of claim 1 wherein each Z is substituted methyl.
3. The oligomeric compound of claim 2 wherein each substituted methyl is, independently, substituted with F, NJ 1 J 2 , N 3 , CN, OJ 1 , SJ 1 , O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 or N(H)C(═O)N(H)J 2 , wherein each J 1 and J 2 is, independently H or C 1 -C 6 alkyl.
4. The oligomeric compound of claim 1 wherein each Z is methyl, ethyl or methoxymethyl.
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 monomer having formula II has the configuration:
8. The oligomeric compound of claim 1 wherein each monomer having formula II has the configuration:
9. The oligomeric compound of claim 1 wherein each modified nucleoside has the formula:
10. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate internucleoside linking group.
11. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.
12. The oligomeric compound of claim 1 wherein j and r are each 2.
13. The oligomeric compound of claim 1 wherein q is from about 9 to about 13.
14. The oligomeric compound of claim 1 wherein j and r are each 5.
15. The oligomeric compound of claim 1 wherein q is about 10.
16. The oligomeric compound of claim 1 wherein G and E are each, independently, H or a hydroxyl protecting group.
17. The oligomeric compound of claim 1 wherein one of G and E is a linked conjugate group.
18. The oligomeric compound of claim 1 wherein G and E are each H.