Oligomeric compounds comprising alpha-beta-constrained nucleic acid
The present disclosure provides oligomeric compounds comprising at least one α-β-constrained nucleic acid as provided herein. More particularly, the α-β-constrained nucleic acid provided herein comprise an optionally modified nucleoside with a phosphorus containing constrained internucleoside linkage such as for example a cyclic phosphate internucleoside linkage. The α-β-constrained nucleic acid provided herein are expected to be useful for enhancing one or more properties of oligomeric compounds they are incorporated into such as for example nuclease resistance. In certain 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. An oligomeric compound comprising from 8 to 40 linked monomer subunits wherein at least one of the monomer subunits is a modified nucleotide having Formula II:
wherein independently for each modified nucleotide having Formula II:
T 3 is attached to one of the linked monomer subunits;
T 4 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside linking group attached to one of the linked monomer subunits;
each Bx is a heterocyclic base moiety;
each G 1 and G 2 is, independently, H, OH or a 2′-sugar substituent group selected from halogen and O—[C(R 1 )(R 2 )] j —[(C═O) m -A] j -T;
wherein each R 1 and R 2 is, independently, H, C 1 -C 6 alkyl or halogen;
A is O, S or N(E 1 );
T is 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 or N(E 2 )(E 3 );
E 1 , E 2 and E 3 are each, independently, H, C 1 -C 6 alkyl or substituted C 1 -C 6 alkyl;
i is from 1 to about 6;
m is 0 or 1;
j is 0 or 1;
wherein each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 3 , N(J 3 ) 4 ), ═NJ 3 , SJ 3 , N 3 , CN, OC(=L 2 )J 3 , OC(=L 2 )N(J 3 )(J 4 ) and C(=L 2 )N(J 3 )(J 4 );
L 2 is O, S or NJ 5 ;
each J 3 , J 4 and J 5 is, independently, H or C 1 -C 6 alkyl; and
when j is 1 then T is other than halogen;
one of each X and each Z is CJ 1 J 2 , NJ 2 , S or O and the other of each X and each Z is O;
each J 1 and J 2 is, independently, H, C 1 -C 6 alkyl, C 2 -C 6 alkenyl or C 2 -C 6 alkynyl;
each n is, independently, from 1 to about 30; and
when Z is O and X is O then at least one G 1 and G 2 is other than H, OH or OCH 3 and when Z is O and X is CH 2 or S then at least one G 1 and G 2 is other than H.
2. The oligomeric compound of claim 1 wherein each X is O.
3. The oligomeric compound of claim 1 wherein each X is CH 2 .
4. The oligomeric compound of claim 1 wherein each Z is O.
5. The oligomeric compound of claim 1 wherein each Z is CH 2 .
6. The oligomeric compound of claim 1 wherein each Z is S.
7. The oligomeric compound of claim 1 wherein each Z is NH or NCH 3 .
8. The oligomeric compound of claim 1 wherein one of each G 1 and each G 2 is H and the other of each G 1 and each G 2 is, independently, selected from halogen, OCH 3 , OCF 3 , OCH 2 CH 3 , OCH 2 CF 3 , OCH 2 —CH═CH 2 , O(CH 2 ) 2 —OCH 3 , O(CH 2 ) 2 —O(CH 2 ) 2 —N(CH 3 ) 2 , OCH 2 C(═O)—N(H)CH 3 , OCH 2 C(═O)—N(H)—(CH 2 ) 2 —N(CH 3 ) 2 and OCH 2 —N(H)—C(═NH)NH 2 .
9. The oligomeric compound of claim 1 wherein each G 1 is O(CH 2 ) 2 —OCH 3 and each G 2 is H.
10. The oligomeric compound of claim 1 wherein each G 1 and G 2 is H.
11. The oligomeric compound of claim 1 wherein each Bx is, independently, uracil, thymine, cytosine, 4-N-benzoylcytosine, 5-methyl-cytosine, 4-N-benzoyl-5-methylcytosine, adenine, 6-N-benzoyl adenine, guanine or 2-N-isobutyrylguanine.
12. The oligomeric compound of claim 1 wherein each modified nucleotide having Formula II has the configuration of one of formulas IIa, IIb, IIc or IId:
13. The oligomeric compound of claim 12 wherein each modified nucleotide has the configuration of Formula IIa.
14. The oligomeric compound of claim 12 wherein each modified nucleotide has the configuration of Formula IIb.
15. The oligomeric compound of claim 12 wherein each modified nucleotide has the configuration of Formula IIc.
16. The oligomeric compound of claim 12 wherein each modified nucleotide has the configuration of Formula IId.
17. The oligomeric compound of claim 12 wherein each G 1 and G 2 is H, each X and Z is O, and n is 1.
18. The oligomeric compound of claim 1 wherein T 3 is attached to a 3′-position of a β-D-ribonucleoside, β-D-2′-deoxyribonucleoside or a modified nucleoside.
19. The oligomeric compound of claim 1 wherein T 3 is attached to a modified nucleoside comprising a substituted nucleoside or a bicyclic nucleoside.
20. The oligomeric compound of claim 1 wherein T 4 is H, a hydroxyl protecting group or a linked conjugate group.
21. The oligomeric compound of claim 1 comprising only one modified nucleotide of Formula II.
22. The oligomeric compound of claim 1 wherein the monomer subunits and each modified nucleotide having Formula II are linked together by internucleoside linking groups selected from phosphodiester and phosphorothioate internucleoside linking groups.
23. The oligomeric compound of claim 22 wherein each internucleoside linking group is a phosphorothioate internucleoside linking group.
24. A method of inhibiting gene expression comprising contacting a cell with an oligomeric compound of claim 1 wherein said oligomeric compound is complementary to a target RNA.