Oligomeric compounds comprising tricyclic nucelosides and methods for their use
View Patent ↗The present disclosure provides tricyclic nucleosides, oligomeric compounds comprising at least one of the tricyclic nucleosides and methods of using the oligomeric compounds. The methods provided herein include contacting a cell or administering to an animal at least one of the oligomeric compounds. In certain embodiments, the oligomeric compounds hybridize to a portion of a target RNA resulting in loss of normal function of the target RNA.
1. An oligomeric compound comprising at least one tricyclic nucleoside having formula II:
wherein independently for each of said tricyclic nucleosides having formula II:
Bx is a heterocyclic base moiety;
one of T 1 and T 2 is an internucleoside linking group attaching said tricyclic nucleoside of formula II to said oligomeric compound and the other of T 1 and T 2 is hydroxyl, a protected hydroxyl, a phosphate moiety, a 5′ or 3′-terminal group or an internucleoside linking group attaching said tricyclic nucleoside of formula II to said oligomeric compound;
q 1 , q 2 , q 3 and q 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;
z 1 and z 2 are each, independently, halogen, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, O—C 2 -C 6 alkenyl, O—C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted O—C 1 -C 6 alkyl, substituted O—C 2 -C 6 alkenyl or substituted O—C 2 -C 6 alkynyl;
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, N 3 , CN, OE 1 , N(E 1 )(E 2 ), O—N(E 1 )(E 2 ), C(═O)N(E 1 )(E 2 ), C(═O)—N(E 3 )-(CH 2 ) r —N(E 1 )(E 2 ) and CH 2 —N(H)—C(═NE 3 )[N(E 1 )(E 2 )] wherein each E 1 , E 2 and E 3 is, independently, H, C 1 -C 6 alkyl or a protecting group and r is from 2 to about 6; and
wherein said oligomeric compound comprises from about 8 to about 40 linked monomeric subunits and is complementary to at least a portion of a target RNA; and
wherein at least one of q 1 , q 2 , q 3 , q 4 , z 1 and z 2 is other than H.
2. The oligomeric compound of claim 1 wherein q 3 and q 4 are H for each of said tricyclic nucleosides having formula II.
3. The oligomeric compound of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is other than H for each of said tricyclic nucleosides having formula II.
4. The oligomeric compound of claim 1 wherein at least one of q 1 , q 2 , q 3 and q 4 is fluoro for each of said tricyclic nucleosides having formula II.
5. The oligomeric compound of claim 1 wherein at least one of q 1 and q 2 is fluoro for each of said tricyclic nucleosides having formula II.
6. The oligomeric compound of claim 1 wherein at least one of q 3 and q 4 is fluoro for each of said tricyclic nucleosides having formula II.
7. The oligomeric compound of claim 1 wherein q 1 and q 2 are each fluoro for each of said tricyclic nucleosides having formula II.
8. The oligomeric compound of claim 2 wherein at least one of q 1 , q 2 , q 3 and q 4 is C 1 -C 6 alkyl for each of said tricyclic nucleosides having formula II.
9. The oligomeric compound of claim 8 wherein at least one of q 1 , q 2 , q 3 and q 4 is methyl for each of said tricyclic nucleosides having formula II.
10. The oligomeric compound of claim 1 wherein each q 1 , q 2 , q 3 and q 4 is H.
11. The oligomeric compound of claim 10 wherein z 1 is fluoro for each of said tricyclic nucleosides having formula II.
12. The oligomeric compound of claim 10 wherein z 2 is fluoro for each of said tricyclic nucleosides having formula II.
13. The oligomeric compound of claim 1 wherein z 1 and z 2 are each fluoro for each of said tricyclic nucleosides having formula II.
14. The oligomeric compound of claim 1 , wherein at least one of z 1 and z 2 is O—C 1 -C 6 alkyl or substituted O—C 1 -C 6 alkyl for each of said tricyclic nucleosides having formula II.
15. The oligomeric compound of claim 1 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.
16. The oligomeric compound of claim 1 wherein each internucleoside linking group is a phosphorothioate.
17. A tricyclic nucleoside having formula III:
wherein:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is H or a hydroxyl protecting group and the other of T 3 and T 4 is H, a hydroxyl protecting group or a reactive phosphorus group;
q 1 , q 2 , q 3 and q 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;
z 1 and z 2 are each, independently, halogen, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, O—C 2 -C 6 alkenyl, O—C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted O—C 1 -C 6 alkyl, substituted O—C 2 -C 6 alkenyl or substituted O—C 2 -C 6 alkynyl;
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, N 3 , CN, OE 1 , N(E 1 )(E 2 ), O—N(E 1 )(E 2 ), C(═O)N(E 1 )(E 2 ), C(═O)—N(E 3 )-(CH 2 ) r —N(E 1 )(E 2 ) and CH 2 —N(H)—C(═NE 3 )[N(E 1 )(E 2 )] wherein each E 1 , E 2 and E 3 is, independently, H, C 1 -C 6 alkyl or a protecting group and r is from 2 to about 6; and
wherein at least one of q 1 , q 2 , q 3 , q 4 , z 1 and z 2 is other than H.
18. The tricyclic nucleoside of claim 17 wherein at least one of q 1 , q 2 , q 3 and q 4 is other than H.
19. A method comprising contacting a cell with an oligomeric compound, wherein said oligomeric compound comprises at least one region of at least 2 contiguous β-D-2′-deoxyribonucleosides and at least one region of from 1 to about 5 contiguous tricyclic nucleosides wherein each tricyclic nucleoside has formula II:
wherein independently for each of said tricyclic nucleosides having formula II:
Bx is a heterocyclic base moiety;
one of T 1 and T 2 is an internucleoside linking group attaching said tricyclic nucleoside of formula II to said oligomeric compound and the other of T 1 and T 2 is hydroxyl, a protected hydroxyl, a phosphate moiety, a 5′ or 3′-terminal group or an internucleoside linking group attaching said tricyclic nucleoside of formula II to said oligomeric compound;
q 1 , q 2 , q 3 and q 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;
z 1 and z 2 are each, independently, halogen, C 1 -C 6 alkyl, O—C 1 -C 6 alkyl, O—C 2 -C 6 alkenyl, O—C 2 -C 6 alkynyl, substituted C 1 -C 6 alkyl, substituted O—C 1 -C 6 alkyl, substituted O—C 2 -C 6 alkenyl or substituted O—C 2 -C 6 alkynyl;
wherein each substituted group is, independently, mono or poly substituted with optionally protected substituent groups independently selected from halogen, oxo, N 3 , CN, OE 1 , N(E 1 )(E 2 ), O—N(E 1 )(E 2 ), C(═O)N(E 1 )(E 2 ), C(═O)—N(E 3 )-(CH 2 ) r —N(E 1 )(E 2 ) and CH 2 —N(H)—C(═NE 3 )[N(E 1 )(E 2 )] wherein each E 1 , E 2 and E 3 is, independently, H, C 1 -C 6 alkyl or a protecting group and r is from 2 to about 6; and
wherein said oligomeric compound comprises from about 8 to about 40 linked monomeric subunits and is complementary to at least a portion of a target RNA.
20. The method of claim 19 wherein q 3 and q 4 are H for each of said tricyclic nucleosides having formula II.