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. A method comprising administering an oligomeric compound to an animal, wherein said oligomeric compound is a gapped oligomeric compound comprising two external regions separated by an internal region, wherein the internal region comprises about 8 to about 12 contiguous β-D-2′-deoxyribonucleosides and each external region comprises from 1 to 3 contiguous tricyclic nucleosides wherein each tricyclic nucleoside has formula II:
wherein independently for each of said tricyclic nucleoside 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;
q1, q2, q3 and q4 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;
z1 and z2 are each, independently, H, 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 monomeric subunits that are linked by phosphorothioate internucleoside linking groups and wherein said oligomeric compound is complementary to at least a portion of a target RNA.
2. The method of claim 1 wherein q1, q2, q3, q4, z1 and z2 are each H for each of said tricyclic nucleoside having formula II.
3. The method of claim 1 wherein at least one of q1, q2, q3, q4, z1 and z2 is other than H for each of said tricyclic nucleoside having formula II.
4. The method of claim 1 wherein each external region comprises 2 tricyclic nucleosides of formula II and the internal region comprises 10 β-D-2′-deoxyribonucleosides.
5. The method of claim 1 wherein said animal is a human.
6. The method of claim 1 wherein said target RNA is human mRNA.