5′-modified bicyclic nucleic acid analogs
View Patent ↗The present invention provides 5′-modified bicyclic nucleoside analogs and oligomeric compounds comprising at least one of these nucleoside analogs. In preferred embodiments the nucleoside analogs have either (R) or (S)-chirality at the 5′-carbon. These bicyclic nucleoside analogs are useful for enhancing properties of oligomeric compounds including for example enhanced nuclease resistance.
1. A bicyclic nucleoside having the formula:
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;
Z is 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, substituted C 2 -C 6 alkynyl or substituted acyl (—C(═O)—);
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, 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 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)NJ 1 J 2 , N(H)C(═NH)NR 1 R 2 or N(H)C(═X)N(H)J 2 wherein X is O or S; and
each J 1 and J 2 is, independently, H, 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, C 1 -C 6 aminoalkyl, substituted C 1 -C 6 aminoalkyl or a protecting group.
2. The bicyclic nucleoside of claim 1 wherein Z is substituted C 1 -C 6 alkyl.
3. The bicyclic nucleoside of claim 2 wherein Z is substituted methyl.
4. The bicyclic nucleoside of claim 3 wherein each of the substituent groups is, independently, F, NJ 1 J 2 , N 3 , CN, OJ 1 , SJ 1 , O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 or N(H)C(═O)N(H)J 2 .
5. The bicyclic nucleoside of claim 4 wherein each J 1 and J 2 is, independently H or C 1 -C 6 alkyl.
6. The bicyclic nucleoside of claim 1 wherein Z is methyl, ethyl or methoxymethyl.
7. The bicyclic nucleoside of claim 6 wherein Z is methyl.
8. The bicyclic nucleoside of claim 1 wherein Z is ethenyl.
9. The bicyclic nucleoside of claim 1 wherein Z is substituted acyl.
10. The bicyclic nucleoside of claim 9 wherein Z is C(═O)NJ 1 J 2 .
11. The bicyclic nucleoside of claim 1 wherein at least one of T 1 and T 2 is a hydroxyl protecting group.
12. The bicyclic nucleoside of claim 11 wherein each of said hydroxyl protecting groups is, independently, selected from acetyl, t-butyl, t-butoxymethyl, methoxymethyl, tetrahydropyranyl, 1-ethoxyethyl, 1-(2-chloroethoxy)ethyl, 2-trimethylsilylethyl, p-chlorophenyl, 2,4-dinitrophenyl, benzyl, benzoyl, p-phenylbenzoyl, 2,6-dichlorobenzyl, diphenylmethyl, p-nitrobenzyl, triphenylmethyl (trityl), 4,4′-dimethoxytrityl, trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triphenylsilyl, triisopropylsilyl, benzoylformate, chloroacetyl, trichloroacetyl, trifluoroacetyl, pivaloyl, 9-fluorenylmethyl carbonate, mesylate, tosylate, triflate, trityl, monomethoxytrityl, dimethoxytrityl, trimethoxytrityl, 9-phenylxanthine-9-yl (Pixyl) and 9-(p-methoxyphenyl)xanthine-9-yl (MOX).
13. The bicyclic nucleoside of claim 11 wherein T 1 is acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl or 4,4′-dimethoxytrityl.
14. The bicyclic nucleoside of claim 1 wherein T 2 is a reactive phosphorus group.
15. The bicyclic nucleoside of claim 14 wherein the reactive phosphorus group is diisopropylcyanoethoxy phosphoramidite or H-phosphonate.
16. The bicyclic nucleoside of claim 15 wherein T 2 is diisopropylcyanoethoxy phosphoramidite and T 1 is 4,4′-dimethoxytrityl.
17. The bicyclic nucleoside of claim 1 having the configuration:
18. The bicyclic nucleoside of claim 1 having the configuration:
19. An oligomeric compound having at least one monomer of the formula:
wherein
Bx is a heterocyclic base moiety;
T 3 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside linking group attached to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound;
T 4 is H, a hydroxyl protecting group, a linked conjugate group or an internucleoside linking group attached to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound;
Z is 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, substituted C 2 -C 6 alkynyl or substituted acyl;
wherein each substituted group is mono or poly substituted with substituent groups independently selected from halogen, 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 , SJ 1 , NJ 1 J 2 , N 3 , COOJ 1 , CN, O—C(═O)NJ 1 J 2 , N(H)C(═NH)NR 1 R 2 or N(H)C(═X)N(H)J 2 wherein X is O or S;
each J 1 and J 2 is, independently, H, 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, C 1 -C 6 aminoalkyl, substituted C 1 -C 6 aminoalkyl or a protecting group; and
wherein at least one of T 3 and T 4 is an internucleoside linking group attached to a nucleoside, a nucleotide, an oligonucleoside, an oligonucleotide, a monomeric subunit or an oligomeric compound.
20. The oligomeric compound of claim 19 wherein each Z is a substituted C 1 -C 6 alkyl.
21. The oligomeric compound of claim 20 wherein each Z is substituted methyl.
22. The oligomeric compound of claim 21 wherein each of said substituent groups is, independently, F, NJ 1 J 2 , N 3 , CN, OJ 1 , SJ 1 , O—C(═O)NJ 1 J 2 , N(H)C(═NH)NJ 1 J 2 or N(H)C(═O)N(H)J 2 .
23. The oligomeric compound of claim 22 wherein each J 1 and J 2 is, independently H or C 1 -C 6 alkyl.
24. The oligomeric compound of claim 19 wherein each Z is methyl, ethyl or methoxymethyl.
25. The oligomeric compound of claim 24 wherein each Z is methyl.
26. The oligomeric compound of claim 19 wherein each Z is ethenyl.
27. The oligomeric compound of claim 19 wherein each Z is substituted acyl.
28. The oligomeric compound of claim 27 wherein each Z is C(═O)NJ 1 J 2 .
29. The oligomeric compound of claim 19 wherein one T 3 is H or a hydroxyl protecting group.
30. The oligomeric compound of claim 19 wherein one T 4 is H or a hydroxyl protecting group.
31. The oligomeric compound of claim 19 wherein at least one T 3 is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.
32. The oligomeric compound of claim 19 wherein at least one T 4 is an internucleoside linking group attached to a nucleoside, a nucleotide or a monomeric subunit.
33. The oligomeric compound of claim 19 wherein at least one T 3 is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.
34. The oligomeric compound of claim 19 wherein at least one T 4 is an internucleoside linking group attached to an oligonucleoside or an oligonucleotide.
35. The oligomeric compound of claim 19 wherein at least one T 3 is an internucleoside linking group attached to an oligomeric compound.
36. The oligomeric compound of claim 19 wherein at least one T 4 is an internucleoside linking group attached to an oligomeric compound.
37. The oligomeric compound of claim 19 wherein at least one monomer has the configuration:
38. The oligomeric compound of claim 19 wherein at least one monomer has the configuration:
39. The oligomeric compound of claim 19 wherein at least one of T 3 and T 4 comprises an internucleoside linking group selected from phosphodiester or phosphorothioate.
40. The oligomeric compound of claim 19 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate.
41. The oligomeric compound of claim 19 comprising at least one region of at least two contiguous monomers of said formula.
42. The oligomeric compound of claim 41 comprising at least two regions of at least two contiguous monomers of said formula.
43. The oligomeric compound of claim 42 comprising a gapped oligomeric compound.
44. The oligomeric compound of claim 19 comprising from about 8 to about 40 nucleosides and/or modified nucleosides or mimetics in length.
45. The oligomeric compound of claim 19 comprising from about 8 to about 20 nucleosides and/or modified nucleosides or mimetics in length.
46. The oligomeric compound of claim 19 comprising from about 10 to about 16 nucleosides and/or modified nucleosides or mimetics in length.
47. The oligomeric compound of claim 19 comprising from about 10 to about 14 nucleosides and/or modified nucleosides or mimetics in length.
48. A method of inhibiting gene expression comprising contacting one or more cells, a tissue or an animal with an oligomeric compound of claim 19 .
49. The oligomeric compound of claim 19 wherein each monomer has the configuration:
50. The oligomeric compound of claim 19 wherein each monomer has the configuration: