Oligomeric compounds comprising 4′-thionucleosides for use in gene modulation

1. An oligomeric compound having at least one 4′-thionucleoside of formula IIa:

wherein, independently, for each 4′-thionucleoside of formula IIa:

one of T 3 and T 4 is an internucleoside linking group linking the 4′-thionucleoside of formula IIa to the oligomeric compound and the other of T 3 and T 4 is H, a protecting group, a conjugate group or an internucleoside linking group linking the 4′-thionucleoside of formula IIa to the oligomeric compound;

Bx is hydrogen or a nucleobase;

X is fluoro, substituted or unsubstituted O—C 1 -C 12 alkyl, substituted or unsubstituted O—C 2 -C 12 alkenyl, or substituted or unsubstituted O—C 2 -C 12 alkynyl.

2. The oligomeric compound of claim 1 , wherein X is a group of formula Ia or Ib:

wherein:

R b is O;

R d is a single bond, O, S or C(═O);

R e is C 1 -C 10 alkyl, N(R k )(R m ), N(R k )(R n ), N═C(R p )(R q ), N═C(R p )(R r ) or has formula Ic;

R p , and R q are each independently hydrogen or C 1 -C 10 alkyl;

R r is R x -R y ;

each R s , R t , R u and R v is, independently, hydrogen, C(O)R w , substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, alkylsulfonyl, arylsulfonyl, a chemical functional group or a conjugate group, wherein the substituent groups are selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl and alkynyl;

or optionally, R u and R v , together form a phthalimido moiety with the nitrogen atom to which they are attached;

each R w is, independently, substituted or unsubstituted C 1 -C 13 alkyl, trifluoromethyl, cyanoethyloxy, methoxy, ethoxy, t-butoxy, allyloxy, 9-fluorenylmethoxy, 2-(trimethylsilyl)-ethoxy, 2,2,2-trichloroethoxy, benzyloxy, butyryl, iso-butyryl, phenyl or aryl;

R k is hydrogen, an amino protecting group or R x -R y ;

R p is hydrogen, an amino protecting group or R x -R y ;

R x is a bond or a linking moiety;

R y is a chemical functional group, a conjugate group or a solid support medium;

each R m and R n is, independently, H, an amino protecting group, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl, wherein the substituent groups are selected from hydroxyl, amino, alkoxy, carboxy, benzyl, phenyl, nitro, thiol, thioalkoxy, halogen, alkyl, aryl, alkenyl, alkynyl; NH 3 + , N(R u )(R v ), guanidino and acyl where said acyl is an acid amide or an ester;

or R m and R n , together, are an amino protecting group, are joined in a ring structure that optionally includes an additional heteroatom selected from N and O or are a chemical functional group;

R i is OR z , SR z , or N(R z ) 2 ;

each R z is, independently, H, C 1 -C 8 alkyl, C 1 -C 8 haloalkyl, C(═NH)N(H)R u , C(═O)N(H)R u or OC(═O)N(H)R u ;

R f , R g and R h comprise a ring system having from about 4 to about 7 carbon atoms or having from about 3 to about 6 carbon atoms and 1 or 2 heteroatoms wherein said heteroatoms are selected from oxygen, nitrogen and sulfur and wherein said ring system is aliphatic, unsaturated aliphatic, aromatic, or saturated or unsaturated heterocyclic;

R j is alkyl or haloalkyl having 1 to about 10 carbon atoms, alkenyl having 2 to about 10 carbon atoms, alkynyl having 2 to about 10 carbon atoms, aryl having 6 to about 14 carbon atoms, N(R k )(R m )OR k , halo, SR k or CN;

m a is 1 to about 10;

each mb is, independently, 0 or 1;

mc is 0 or an integer from 1 to 10;

md is an integer from 1 to 10;

me is from 0, 1 or 2; and

provided that when mc is 0, md is greater than 1.

3. The oligomeric compound of claim 1 , wherein at least one of T 3 or T 4 is a phosphodiester internucleoside linkage.

4. The oligomeric compound of claim 3 , wherein each internucleoside linkage is a phosphodiester internucleoside linkage.

5. The oligomeric compound of claim 1 , wherein at least one of T 3 or T 4 is a phosphorothioate internucleoside linkage.

6. The oligomeric compound of claim 5 , wherein each internucleoside linkage is a phosphorothioate internucleoside linkage.

7. The oligomeric compound of claim 1 , wherein X is selected from fluoro or substituted or unsubstituted O—C 1 -C 12 alkyl.

8. The oligomeric compound of claim 1 , wherein X is fluoro.

9. The oligomeric compound of claim 1 , wherein X is O—CH 3 .

10. The oligomeric compound of claim 1 , wherein X is O—CH 2 CH 2 —O—CH 3 .

11. The oligomeric compound of claim 1 , wherein X is O-allyl, O—(CH 2 ) ma —O—N(R m )(R n ) or O—CH 2 —C(═O)—N(R m )(R n );

wherein:

each R m and R n is, independently, H, an amino protecting group, substituted or unsubstituted C 1 -C 10 alkyl, substituted or unsubstituted C 2 -C 10 alkenyl, substituted or unsubstituted C 2 -C 10 alkynyl; and

ma is from 1 to about 10.

12. The oligomeric compound of claim 1 wherein each X is identical for each 4′-thionucleoside of formula IIa.

13. The oligomeric compound of claim 1 comprising between 8 and 80 nucleosides.

14. The oligomeric compound of claim 1 comprising between 8 and 50 nucleosides.

15. The oligomeric compound of claim 1 comprising between 8 and 30 nucleosides.

16. The oligomeric compound of claim 1 comprising between 10 and 30 nucleosides.

17. The oligomeric compound of claim 1 comprising between 15 and 30 nucleosides.

18. The oligomeric compound of claim 1 comprising between 15 and 25 nucleosides.

19. The oligomeric compound of claim 1 comprising a plurality of ribonucleosides.

20. The oligomeric compound of claim 1 wherein each nucleoside that is not a 4′-thionucleoside of formula IIa is a ribonucleoside.