Cyclohexenyl nucleic acids analogs
The present disclosure describes cyclohexenyl nucleic acid analogs, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, cyclohexenyl nucleic acid analogs are provided, having one or more chiral substituents, that are expected to be useful for enhancing properties of oligomeric compounds including nuclease resistance and binding affinity. In some embodiments, the oligomeric compounds provided herein hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
1. A cyclohexenyl nucleic acid analog having Formula I:
wherein:
Bx is a heterocyclic base moiety selected from uracil, thymine, cytosine, 5-methyl-cytosine, adenine and guanine wherein exocyclic amino groups are optionally protected;
X is fluoro;
one of T 1 and T 2 is H or a hydroxyl protecting group and the other of T 1 and T 2 is H, a hydroxyl protecting group or a reactive phosphorus group;
q 1 , q 2 , q 3 and q 4 are each, independently, H, 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 or substituted C 2 -C 6 alkynyl;
j 1 , j 2 , j 3 and j 4 are each, independently, H, halogen, 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 or substituted C 2 -C 6 alkynyl; and
wherein 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(═O)J 1 and CN, wherein each J 1 and J 2 is, independently, H or C 1 -C 6 alkyl.
2. The cyclohexenyl nucleic acid analog of claim 1 wherein q 1 , q 2 , q 3 and q 4 are each H.
3. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is substituted C 1 -C 6 alkyl.
4. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is substituted C 1 -C 6 alkyl comprising at least one substituent group selected from fluoro or OCH 3 .
5. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is C 1 -C 6 alkyl.
6. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is methyl.
7. The cyclohexenyl nucleic acid analog of claim 1 wherein j 1 , j 2 , j 3 and j 4 are each H.
8. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is substituted C 1 -C 6 alkyl.
9. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is substituted C 1 -C 6 alkyl comprising at least one substituent group selected from fluoro or OCH 3 .
10. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is C 1 -C 6 alkyl.
11. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is methyl or fluoro.
12. The cyclohexenyl nucleic acid analog of claim 1 wherein at least one of j 1 , j 2 , j 3 and j 4 is fluoro.
13. The cyclohexenyl nucleic acid analog of claim 1 wherein q 1 , q 2 , q 3 , q 4 , j 1 , j 2 , j 3 and j 4 are each H.
14. The cyclohexenyl nucleic acid analog of claim 13 wherein X and J 2 are each fluoro.
15. The cyclohexenyl nucleic acid analog of claim 13 having Formula II:
wherein:
Bx is a heterocyclic base moiety; and
one of T 1 and T 2 is H or a hydroxyl protecting group and the other of T 1 and T 2 is H, a hydroxyl protecting group or a reactive phosphorus group.
16. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.
17. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is 4,4′-dimethoxytrityl.
18. The cyclohexenyl nucleic acid analog of claim 1 wherein T 2 is a reactive phosphorus group.
19. The cyclohexenyl nucleic acid analog of claim 1 wherein T 2 is a reactive phosphorus group selected from diisopropylcyanoethoxy phosphoramidite and H-phosphonate.
20. The cyclohexenyl nucleic acid analog of claim 1 wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.