Nucleic acid chemical modifications

Abstract

The present invention provides nucleosides of formula (1) and oligonucleotides comprising at least on nucleoside of formula (2): Another aspect of the invention relates to a method of inhibiting the expression of a gene in cell, the method comprising (a) contacting an oligonucleotide of the invention with the cell; and (b) maintaining the cell from step (a) for a time sufficient to obtain degradation of the mRNA of the target gene.

1 . A nucleoside of formula (1): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 one of D 1  and D 2  is H, or a hydroxyl protecting group, and the other of D 1  and D 2  is H, a hydroxyl protecting group, or a reactive phosphorus group; 
 m is an integer from 1 to 15; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal nucleobase; 
 Q is selected from the group consisting of O, S, NR 10 , and CH 2 ; 
 W is absent, O, S or NR′; 
 V is a straight or branched, substituted or unsubstituted alkylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, of which one or more methylenes can be interrupted by O, S, S(O), SO 2 , N(R′), C(O), phosphorus containing linkage, aryl, heteroaryl, heterocyclic, or cycloalkyl; 
 R′ is hydrogen, acyl, unsubstituted or substituted aliphatic; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 40 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form an unsubstituted or substituted heterocyclic ring; 
 R 40  and R 50  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic; 
 provided that when W is O and Z is OR 10 , V is not an unsubstituted alkylene or an unsubstituted alkoxylene. 
 
     
     
         2 . The nucleoside of claim,  1  represented by formula (3): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 one of D 1  and D 2  is H or a hydroxyl protecting group and the other of D 1  and D 2  is H, a hydroxyl protecting group, or a reactive phosphorus group; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 Q is selected from the group consisting of O, S, NR 10 , and CH 2 ; 
 W is absent, O, S or NR′; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted and substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , —N—NR 20 R 30 , or ═N—NR 20 C(O)R 10 ; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 40 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  are each independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring; 
 R 40  and R 50  are each independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic. 
 
     
     
         3 . The nucleoside of  claim 1 , represented by formula (5): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 one of D 1  and D 2  is H, or a hydroxyl protecting group and the other of D 1  and D 2  is H, a hydroxyl protecting group, or a reactive phosphorus group; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, NR 20 , —N—NR 20 R 30 , or —N—NR 20 C(O)R 10 ; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 40 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring; 
 R 40  and R 50  for each occurrence are independently selected from the group consisting of hydrogen, acyl, aliphatic or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, an unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic. 
 
     
     
         4 . The nucleoside of  claim 1 , represented by formula (7): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 one of D 1  and D 2  is H, or a hydroxyl protecting group and the other of D 1  and D 2  is H, a hydroxyl protecting group, or a reactive phosphorus group; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 100  and R 200  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or ═NR 20 ; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or ═NR 20 ; 
 R 500 -R 800  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; 
 Q 10  is O, S, or NR 20 ; 
 R 20  and R 30  are each independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring;
 R 10  and R 10 ′ are independently hydrogen, aliphatic, substituted aliphatic, aryl, heteroaryl, or heterocyclic; 
 s and t are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that s and t are not both 0; and 
 u and v are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that u and v are not both 0. 
 
     
     
         5 . The nucleoside of  claim 1 , represented by formula (9): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 one of D 1  and D 2  is H, or a hydroxyl protecting group and the other of D 1  and D 2  is H, a hydroxyl protecting group, or a reactive phosphorus group; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 100  and R 200  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or ═NR 20 ; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or ═NR 20 ; 
 Q 10  is O, S, or NR 20 ; 
 R 20  and R 30  are each independently selected from the group consisting of hydrogen, acyl, aliphatic or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring;
 R 10  and R 10 ′ are independently hydrogen, aliphatic, substituted aliphatic, aryl, heteroaryl, or heterocyclic; and 
 s and t are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that s and t are not both 0. 
 
     
     
         6 . An oligonucleotide comprising at least one nucleoside of formula (2): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 m is an integer from 1 to 15; 
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal nucleobase; 
 Q is selected from the group consisting of O, S, NR 10 , and CH 2 ; 
 W is absent, O, S or NR′; 
 V is a straight or branched, substituted or unsubstituted alkylene, substituted or unsubstituted alkoxylene, substituted or unsubstituted alkenylene, or substituted or unsubstituted alkynylene, wherein the backbone of the alkylene, alkoxylene, alkenylene, or alkynylene may contain one or more of O, S, S(O), SO 2 , N(R′), C(O), substituted or unsubstituted aryl, substituted or unsubstituted heteroaryl, substituted or unsubstituted heterocyclic, or substituted or unsubstituted cycloalkyl; 
 R′ is hydrogen, acyl, unsubstituted or substituted aliphatic; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 40 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form an unsubstituted or substituted heterocyclic ring; 
 R 40  and R 50  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic; 
 provided that when W is O and Z is OR 10 , V is not an unsubstituted alkylene or an unsubstituted alkoxylene. 
 
     
     
         7 . The oligonucleotide of  claim 6 , wherein the nucleoside of formula (2) is represented by a nucleoside of formula (4): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 Q is selected from the group consisting of O, S, NR 10 , and CH 2 ; 
 W is absent, O, S or NR′; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted and substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , or ═N—NR 20 C(O)R 10 ; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 40 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring; 
 R 40  and R 50  are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic. 
 
     
     
         8 . The oligonucleotide of  claim 6 , wherein the nucleoside of formula (2) is represented by a nucleoside of formula (6): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, NR 20 , —N—NR 20 R 30 , or ═N—NR 20 C(O)R 10 ; 
 Z is selected from the group consisting of OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       NR 20 R 30 , CONR 20 R 30 , CON(H)NR 20 R 30 , ONR 20 R 30 , CON(H)N═CR 40 R 50 , N(R 20 )C(═NR 30 )NR 20 R 30 , N(R 20 )C(O)NR 20 R 30 , N(R 20 )C(S)NR 20 R 30 , OC(O)NR 20 R 30 , SC(O)NR 20 R 30 , N(R 20 )C(S)OR 10 , N(R 20 )C(O)OR 10 , N(R 20 )C(O)SR 10 , N(R 20 )N═CR 40 R 50 , ON═CR 10 R 50 , SO 2 R 10 , SOR 10 , SR 10 , and substituted or unsubstituted heterocyclic;
 R 20  and R 30  for each occurrence are independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring; 
 R 40  and R 50  for each occurrence are independently selected from the group consisting of hydrogen, acyl, aliphatic or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , and NR 10 R 10 ′; and 
 R 10  and R 10 ′ are each independently hydrogen, an unsubstituted or substituted aliphatic, aryl, heteroaryl, or heterocyclic. 
 
     
     
         9 . The oligonucleotide of  claim 6 , wherein the nucleoside of formula (2) is represented by a nucleoside of formula (8): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 100  and R 200  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or ═NR 20 ; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , ═N—NR 20 C(O)R 10  or —NR 20 ; 
 R 500 -R 800  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; 
 Q 10  is O, S, or NR 20 ; 
 R 20  and R 30  are each independently selected from the group consisting of hydrogen, acyl, unsubstituted or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring;
 R 10  and R 10 ′ are independently hydrogen, aliphatic, substituted aliphatic, aryl, heteroaryl, or heterocyclic; 
 s and t are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that s and t are not both 0; and 
 u and v are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that u and v are not both 0. 
 
     
     
         10 . The oligonucleotide of  claim 6 , wherein the nucleoside of formula (2) is represented by a nucleoside of formula (10): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, wherein:
 B is selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, a natural nucleobase, a modified nucleobase, and a universal base; 
 R 100  and R 200  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 100  and R 200  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or —NR 20 ; 
 R 300  and R 400  are each independently selected from the group consisting of hydrogen, unsubstituted or substituted aliphatic, aryl, halogen, heteroaryl, and heterocyclic; or R 300  and R 400  are taken together with the atom to which they are bound to form a carbonyl, thiocarbonyl, ═NR 20 , ═N—NR 20 R 30 , —N—NR 20 C(O)R 10  or —NR 20 ; 
 Q 10  is O, S, or NR 20 ; 
 R 20  and R 30  are each independently selected from the group consisting of hydrogen, acyl, aliphatic or substituted aliphatic, aryl, heteroaryl, heterocyclic, OR 10 , COR 10 , CO 2 R 10 , 
 
       
         
           
           
               
               
           
         
       
       and NR 10 R 10 ′; or R 20  and R 30  are taken together with the atom to which they are bound to form a heterocyclic ring;
 R 10  and R 10 ′ are independently hydrogen, aliphatic, substituted aliphatic, aryl, heteroaryl, or heterocyclic; and 
 s and t are independently for each occurrence 0, 1, 2, 3, 4, 5 or 6, provided that s and t are not both 0. 
 
     
     
         11 . The oligonucleotide of  claim 6 , wherein the nucleoside of formula (2) is selected from the group consisting of: 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
       and isomers thereof, wherein:
 R 1 , R 2 , R 3 , R 4 , R 6 , R 7 , R 8  and R 9  are each independently selected form the group consisting of alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl and acyl; 
 B is an optionally substituted natural or non-natural nucleobase or a universal nucleobase; 
 Q and Y are each independently selected from the group consisting of O, S, CR′ 2 , and NR″, where R′ is hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, or heterocycloalkyl, and R″ is hydrogen, alkyl, aryl, cycloalkyl, heteroaryl, heterocycloalkyl or acyl; and 
 m, n and p are each independently an integer from 1 to 10. 
 
     
     
         12 . The oligonucleotide of  claim 6 , wherein said oligonucleotide comprises at least one non-phosphodiester backbone linkage. 
     
     
         13 . The oligonucleotide of  claim 12 , wherein the non-phosphodiester of said non-phosphodiester backbone linkage is selected from the group consisting of phosphorothioate, phosphorodithioate, alkyl-phosphonate and phosphoramidate. 
     
     
         14 . The oligonucleotide of  claim 12 , the non-phosphodiester backbone linkage is placed (a) between nucleosides of positions 1 and 2, and/or (b) between the 3′-terminal nucleosides. 
     
     
         15 . The oligonucleotide of  claim 6 , wherein said oligonucleotide comprises at least one ligand conjugate. 
     
     
         16 . The oligonucleotide of  claim 6 , wherein said oligonucleotide is a double-stranded oligonucleotide comprising a first strand and a second strand. 
     
     
         17 . The oligonucleotide of  claim 16 , wherein the nucleoside of formula (2) is present either the first strand or the second strand. 
     
     
         18 . The oligonucleotide of  claim 17 , wherein said first strand is the sense strand. 
     
     
         19 . The oligonucleotide of  claim 17 , wherein said second strand is the antisense strand. 
     
     
         20 . The oligonucleotide of  claim 17 , wherein the nucleoside of formula (2) is present in both strands.