5′-substituted bicyclic nucleosides and oligomeric compounds prepared therefrom
View Patent ↗Provided herein are novel 5′-(S)—CH 3 substituted bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using the oligomeric compounds. More particularly, the furanose ring of each of the novel 5′-(S)—CH 3 substituted bicyclic nucleosides includes a 2′ to 4′ bridging group. The 5′-(S)—CH 3 substituted bicyclic nucleosides are expected to be useful for enhancing one or more properties of the oligomeric compounds they are incorporated into such as for example increasing the binding affinity. 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. A bicyclic nucleoside having Formula I:
wherein:
Bx is a heterocyclic base moiety;
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;
G is —C(═O)—N(R 7 )—C(R 1 R 2 )—, —C(R 1 R 2 )—N(R 7 )—C(R 3 R 4 )—, —C(R 1 R 2 )—N(R 7 )—O—, —C(R 1 R 2 )—O—N(R 7 )—, —C(R 1 R 2 )—N(OR 3 )—, —C(R 1 R 2 )—C(R 3 R 4 )—N(R 7 )—, —C(R 1 R 2 )—O—C(R 3 R 4 )—, —C(R 1 R 2 )—O—C(R 3 R 4 )—O—, or —C(R 1 R 2 )—C(R 3 R 4 )—C(R 5 R 6 )—O—;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently, H, F, 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 or CN;
R 7 is H, C 1 -C 6 alkyl or an amino protecting group;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 3 , N(J 3 )(J 4 ), ═NJ 3 , SJ 3 , N 3 , CN, OC(=L)J 3 , OC(=L)N(J 3 )(J 4 ) and C(=L)N(J 3 )(J 4 );
L is O, S or NJ 5 ; and
each J 1 , J 3 , J 4 and J 5 is, independently, H or C 1 -C 6 alkyl.
2. The bicyclic nucleoside of claim 1 wherein:
G is —C(═O)—NH—CH 2 —, —C(═O)—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—O—, —CH 2 —O—N(CH 3 )—, —CH 2 —N(CH 3 )—CH 2 —, —CH 2 —CH 2 —NH—, —CH 2 —N(OCH 3 )—, —CH 2 —N(O—(CH 2 ) 2 OCH 3 )—, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —O— or —CH 2 —O—CH 2 —O—.
3. The bicyclic nucleoside of claim 1 wherein at least one of T 1 and T 2 is selected from acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl and dimethoxytrityl.
4. The bicyclic nucleoside of claim 1 wherein T 1 is 4,4′-dimethoxytrityl.
5. The bicyclic nucleoside of claim 1 wherein T 2 is diisopropylcyanoethoxy phosphoramidite or H-phosphonate.
6. The bicyclic nucleoside of claim 1 wherein T 1 is 4,4′-dimethoxytrityl and T 2 is diisopropylcyanoethoxy phosphoramidite.
7. The bicyclic nucleoside of claim 1 wherein Bx is uracil, 5-thiazolo-uracil, 2-thio-uracil, 5-propynyl-uracil, thymine, 2-amino-thymine, cytosine, 5-methylcytosine, 5-thiazolo-cytosine, 5-propynyl-cytosine, adenine, guanine, 2,6-diaminopurine, 1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), 1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one, 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one, 2H-pyrimido[4,5-b]indol-2-one or H-pyrido[3′,2′:4,5]pyrrolo[2,3-d]pyrimidin-2-one.
8. The bicyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
9. An oligomeric compound comprising at least one bicyclic nucleoside of Formula II:
wherein independently for each bicyclic nucleoside of Formula II:
Bx is a heterocyclic base moiety;
one of T 3 and T 4 is an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound and the other of T 3 and T 4 is H, a hydroxyl protecting group, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside to the oligomeric compound;
G is —C(═O)—N(R 7 )—C(R 1 R 2 )—, —C(R 1 R 2 )—N(R 7 )—C(R 3 R 4 )—, —C(R 1 R 2 )—N(R 7 )—O—, —C(R 1 R 2 )—O—N(R 7 )—, —C(R 1 R 2 )—N(OR 3 )—, —C(R 1 R 2 )—C(R 3 R 4 )—N(R 7 )—, —C(R 1 R 2 )—O—C(R 3 R 4 )—, —C(R 1 R 2 )—O—C(R 3 R 4 )—O—, or —C(R 1 R 2 )—C(R 3 R 4 )—C(R 5 R 6 )—O—;
R 1 , R 2 , R 3 , R 4 , R 5 and R 6 are each independently, H, F 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 , or CN;
R 7 is H, C 1 -C 6 alkyl or an amino protecting group;
each substituted group comprises one or more optionally protected substituent groups independently selected from halogen, OJ 3 , N(J 3 )(J 4 ), ═NJ 3 , SJ 3 , N 3 , CN, OC(=L)J 3 , OC(=L)N(J 3 )(J 4 ) and C(=L)N(J 3 )(J 4 );
L is O, S or NJ 5 ; and
each J 1 , J 3 , J 4 and J 5 is, independently, H or C 1 -C 6 alkyl.
10. The oligomeric compound of claim 9 wherein independently for each bicyclic nucleoside of Formula II:
G is —C(═O)—NH—CH 2 —, —C(═O)—N(CH 3 )—CH 2 —, —CH 2 —N(CH 3 )—O—, —CH 2 —O—N(CH 3 )—, —CH 2 —N(CH 3 )—CH 2 —, —CH 2 —CH 2 —NH—, —CH 2 —N(OCH 3 )—, —CH 2 —N(O—(CH 2 ) 2 OCH 3 )—, —CH 2 —O—CH 2 —, —CH 2 —CH 2 —CH 2 —O— or —CH 2 —O—CH 2 —O—.
11. The oligomeric compound of claim 9 wherein at least one T 3 is a 5′-terminal group and or at least one T 4 is a 3′-terminal group.
12. The oligomeric compound of claim 9 wherein one T 3 or T 4 is a conjugate group or a phosphate moiety.
13. The oligomeric compound of claim 9 wherein one T 3 is a phosphate moiety.
14. The oligomeric compound of claim 9 wherein each Bx is, independently, uracil, 5-thiazolo-uracil, 2-thio-uracil, 5-propynyl-uracil, thymine, 2-amino-thymine, cytosine, 5-methylcytosine, 5-thiazolo-cytosine, 5-propynyl-cytosine, adenine, guanine, 2,6-diaminopurine, 1H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one), 1H-pyrimido[5,4-b][1,4]benzothiazin-2(3H)-one, 9-(2-aminoethoxy)-H-pyrimido[5,4-b][1,4]benzoxazin-2(3H)-one, 2H-pyrimido[4,5-b]indol-2-one or H-pyrido[3′,2′:4,5]-pyrrolo[2,3-d]pyrimidin-2-one.
15. The oligomeric compound of claim 9 wherein each Bx is, independently, uracil, thymine, cytosine, 5-methylcytosine, adenine or guanine.
16. The oligomeric compound of claim 9 comprising at least one region of at least two contiguous bicyclic nucleosides having Formula II located at either the 3′ or the 5′-end of the oligomeric compound.
17. The oligomeric compound of claim 9 comprising from about 8 to about 40 monomers in length.
18. The oligomeric compound of claim 9 comprising a gapped oligomeric compound having at least two regions, each region comprising from 1 to about 5 contiguous bicyclic nucleosides having Formula II, wherein one of said regions of bicyclic nucleosides having Formula II is located externally at the 5′-end and the other of said regions is located externally at the 3′-end and wherein the two external regions are separated by an internal region comprising from about 6 to about 14 monomeric subunits independently selected from nucleosides and modified nucleosides.
19. The oligomeric compound of claim 18 wherein each of said monomer subunits in the internal region is a β-D-2′-deoxyribonucleoside.
20. The oligomeric compound of claim 18 wherein said internal region comprises from about 8 to about 14 contiguous β-D-2′-deoxyribofuranosyl nucleosides.
21. The oligomeric compound of claim 18 wherein said internal region comprises from about 9 to about 12 contiguous β-D-2′-deoxyribofuranosyl nucleosides.
22. The oligomeric compound of claim 9 wherein each internucleoside linking group is, independently, a phosphodiester internucleoside linking group or a phosphorothioate internucleoside linking group.
23. The oligomeric compound claim 9 wherein essentially each internucleoside linking group is a phosphorothioate internucleoside linking group.
24. The bicyclic nucleoside of claim 1 having the formula:
25. The oligomeric compound of claim 9 wherein each bicyclic nucleoside of Formula II has the configuration of the formula: