Provided herein are saturated and unsaturated carbocyclic bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using these oligomeric compounds. The saturated and unsaturated carbocyclic bicyclic nucleosides are useful for enhancing properties of oligomeric compounds includin
Provided herein are saturated and unsaturated carbocyclic bicyclic nucleosides, oligomeric compounds prepared therefrom and methods of using these oligomeric compounds. The saturated and unsaturated carbocyclic bicyclic nucleosides are useful for enhancing properties of oligomeric compounds including nuclease resistance.
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1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q is C(q1)(q2)C(q3)(q4), C(q1)=C(q3), C[═C(q1)(q2)]-C(q3)(q4) or C(q1
1. A bicyclic nucleoside having Formula I: wherein: Bx is a heterocyclic base moiety;one of T1 and T2 is H or a hydroxyl protecting group and the other of T1 and T2 is H, a hydroxyl protecting group or a reactive phosphorus group;Q is C(q1)(q2)C(q3)(q4), C(q1)=C(q3), C[═C(q1)(q2)]-C(q3)(q4) or C(q1)(q2)-C [═(q3)(q4)];q1, q2, q3 and q4 are each, independently, H, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C1-C12 alkoxy, substituted C1-C12 alkoxy, OJ1, SJ1, SOJ1, SO2J1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group; andwherein when Q is C(q1)(q2)C(q3)(q4) and one of q3 or q4 is CH3 then at least one of the other of q3 or q4 or one of q1 and q2 is other than H. 2. The bicyclic nucleoside of claim 1 wherein Q is 4′-C(q1)(q2)C(q3)(q4)-2′. 3. The bicyclic nucleoside of claim 1 wherein Q is 4′-C(q1)(q2)-C[═C(q3)(q4)]-2′. 4. The bicyclic nucleoside of claim 1 wherein Q is 4′-C[═C(q1)(q2)]-C(q3)(q4)-2′. 5. The bicyclic nucleoside of claim 1 wherein Q is 4′-C(q1)=C(q3) -2′. 6. The bicyclic nucleoside of claim 1 wherein q1, q2, q3 and q4, where present, are each H. 7. The bicyclic nucleoside of claim 1 wherein one of q1, q2, q3 and q4 is other than H and the remaining of q1, q2, q3 and q4 are each H. 8. The bicyclic nucleoside of claim 1 wherein two of q1, q2, q3 and q4 are other than H and the remaining of q1, q2, q3 and q4 are each H. 9. The bicyclic nucleoside of claim 1 wherein q1, q2, q3 and q4 where present, are each independently, H, halogen, C1-C6 alkyl or C1-C6 alkoxy. 10. The bicyclic nucleoside of claim 1 wherein q1, q2, q3 and q4, where present, are each independently, H, CH3 or F. 11. The bicyclic nucleoside of claim 1 wherein Bx is uracil, thymine, cytosine, 5-methylcytosine, 5-thiazolo-uracil, 5-thiazolo-cytosine, adenine, guanine, 2,6-diaminopurine, or other substituted or unsubstituted purine or pyrimidine. 12. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxytrityl. 13. The bicyclic nucleoside of claim 1 wherein T2 is diisopropyl-cyanoethoxy phosphoramidite or H-phosphonate. 14. The bicyclic nucleoside of claim 1 wherein T1 is 4,4′-dimethoxytrityl and T2 is diisopropylcyanoethoxy phosphoramidite. 15. The bicyclic nucleoside of claim 1, wherein the bicyclic nucleoside has a configuration according to Formula Ia: 16. The bicyclic nucleoside of claim 15 wherein Q is 4′-C(q1)(q2)C(q3)(q4)-2′. 17. The bicyclic nucleoside of claim 16 wherein Q is 4′-(CH2)2-2 ′. 18. The bicyclic nucleoside of claim 16 wherein one of q3 and q4 is F and the remaining of q1, q2, q3 and q4 are each H. 19. The bicyclic nucleoside of claim 15 wherein Q is 4′-C(q1)=C(q3)-2′. 20. The bicyclic nucleoside of claim 15 wherein Q is 4′-C[═C(q1)(q2)]-C(q3)(q4)-2′. 21. The bicyclic nucleoside of claim 15 wherein Q is 4′-C(q1)(q2) -C[═C(q3)(q4)]-2′. 22. The bicyclic nucleoside of claim 21 wherein Q is 4′—CH2—C(═CH2)-2′. 23. An oligomeric compound comprising at least one bicyclic nucleoside having Formula IV: wherein independently for each bicyclic nucleoside having Formula IV: Bx is a heterocyclic base moiety;one of T3 and T4 is an internucleoside linking group linking the bicyclic nucleoside having Formula IV to the oligomeric compound and the other of T3 and T4 is H, a hydroxyl protecting group, a linked conjugate group, a 5′ or 3′-terminal group or an internucleoside linking group linking the bicyclic nucleoside having Formula IV to the oligomeric compound;Q is C(q1)(q2)C(q3)(q4), C(q1)=C(q3), C[═C(q1)(q2)]-C(q3)(q4) or C(q1)(q2) -C[═C(q3)(q4)];q1, q2, q3 and q4 are each, independently, H, halogen, C1-C12 alkyl, substituted C1-C12 alkyl, C2-C12 alkenyl, substituted C2-C12 alkenyl, C2-C12 alkynyl, substituted C2-C12 alkynyl, C1-C12 alkoxy, substituted C1-C12 alkoxy, OJ1, SJ1, SOJ1, SO2J1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C(═O)NJ1J2, N(H)C(═NH)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;wherein each substituted group is, independently, mono or poly substituted with substituent groups independently selected from halogen, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, OJ1, SJ1, NJ1J2, N3, CN, C(═O)OJ1, C(═O)NJ1J2, C(═O)J1, O—C (═O)NJ1J2, N(H)C(═O)NJ1J2 or N(H)C(═S)NJ1J2;each J1 and J2 is, independently, H, C1-C6 alkyl, C2-C6 alkenyl, C2-C6 alkynyl, C1-C6 aminoalkyl or a protecting group; andwherein when Q is C(q1)(q2)C(q3)(q4) and one of q3 or q4 is CH3 then at least one of the other of q3 or q4 or one of q1 and q2 is other than H. 24. The oligomeric compound of claim 23 wherein for each bicyclic nucleoside having Formula IV, Q is 4′-C(q1)(q2)C(q3)(q4) -2′. 25. The oligomeric compound of claim 23 wherein for each bicyclic nucleoside having Formula IV, Q is 4′-C(q1)(q2)-C[═C(q3)(q4)]-2′. 26. The oligomeric compound of claim 23 wherein for each bicyclic nucleoside having Formula IV, Q is 4′C[═C(q1)(q2)]-C(q3)(q4)-2′. 27. The oligomeric compound of claim 23 wherein for each bicyclic nucleoside having Formula IV, Q is 4′-C(q1)=C(q3)-2′. 28. The oligomeric compound of claim 23 wherein for each bicyclic nucleoside having Formula IV q1, q2, q3 and q4, where present, are each H. 29. The oligomeric compound of claim 23 wherein, independently, for each bicyclic nucleoside having Formula IV one of q1, q2, q3 and q4 is other than H and the remaining of q1, q2, q3 and q4 are each H. 30. The oligomeric compound of claim 23 wherein, independently, for each bicyclic nucleoside having Formula IV two of q1, q2, q3 and q4 are other than H and the remaining of q1, q2, q3 and q4 are each H. 31. The oligomeric compound of claim 23 wherein, independently, for each bicyclic nucleoside having Formula IV q1, q2, q3 and q4 are each, independently, H, halogen, C1-C6 alkyl or C1-C6 alkoxy. 32. The oligomeric compound of claim 23 wherein, independently, for each bicyclic nucleoside having Formula IV q1, q2, q3 and q4 are each, independently, H, CH3 or F. 33. The oligomeric compound of claim 23 wherein each Bx is uracil, thymine, cytosine, 5-methylcytosine, 5-thiazolo-uracil, 5-thiazolo-cytosine, adenine, guanine, 2,6-diaminopurine, or other substituted or unsubstituted purine or pyrimidine. 34. The oligomeric compound of claim 23 wherein at least one of T3 and T4 is a 5′ or 3′-terminal group. 35. The oligomeric compound of claim 23 wherein each bicyclic nucleoside having Formula IV has the configuration of Formula IVa: 36. The oligomeric compound of claim 35 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-C(q1)(q2)C(q3)(q4) -2′. 37. The oligomeric compound of claim 36 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-(CH2)2-2′. 38. The oligomeric compound of claim 36 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′- CH2—CHF-2′. 39. The oligomeric compound of claim 35 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-C(q1)=C(q3)-2′. 40. The oligomeric compound of claim 35 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-C[═C(q1)(q2)]-C(q3)(q4)-2′. 41. The oligomeric compound of claim 35 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-C(q1)(q2)-C[═C(q3)(q4)]-2′. 42. The oligomeric compound of claim 41 wherein for each bicyclic nucleoside having Formula IVa, Q is 4′-CH2—C(═CH2)-2′. 43. The oligomeric compound of claim 23 wherein each internucleoside linking group is, independently, a phosphodiester or a phosphorothioate. 44. The oligomeric compound of claim 23 comprising at least one region of at least two contiguous bicyclic nucleosides having said formula located at either the 3′ or the 5′-end of the oligomeric compound. 45. The oligomeric compound of claim 23 comprising a gapped oligomeric compound having at least two regions, each region comprising from 1 to about 5 contiguous bicyclic nucleosides having Formula IV, wherein one of said regions of bicyclic nucleosides having Formula IV 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. 46. The oligomeric compound of claim 23 comprising from about 8 to about 40 monomers in length. 47. The oligomeric compound of claim 23 comprising from about 8 to about 20 monomers in length. 48. A method for inhibiting gene expression comprising contacting a cell with an oligomeric compound of claim 23, wherein said oligomeric compound comprises from about 8 to about 40 monomeric subunits and is complementary to a target RNA. 49. The method of claim 48 wherein said cell is in an animal. 50. The method of claim 48 wherein said cell is in a human. 51. The method of claim 48 wherein said target RNA is selected from mRNA, pre-mRNA and micro RNA. 52. The method of claim 48 wherein said target RNA is mRNA. 53. The method of claim 48 wherein said target RNA is human mRNA. 54. The method of claim 48 wherein said target RNA is cleaved thereby inhibiting its function. 55. The method of claim 48 further comprising detecting the levels of target RNA.
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