Oligonucleotides comprising acyclic and abasic nucleosides and analogs

Abstract

These monomers are useful for modifying of oligonucleotides at one or more positions. This invention also relates to a method of inhibiting the expression of a target gene in a cell. The method comprises contacting the cell with an oligonucleotide having one or more of the above formula (IV′).

We claim: 
     
         1 . A monomer of formula (I′): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, 
       wherein:
 each B is independently H or a nucleobase; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  is independently for each occurrence H, halo, OR 13 , N(R′)(R″), alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, ω-amino alkyl, ω-hydroxy alkyl, ω-hydroxy alkenyl, or ω-hydroxy alkynyl, each of which can be optionally substituted; 
 R 11  and R 12  are independently for each occurrence H, protecting group, a reactive phosphorus group, or solid support; 
 R 13  is independently for each occurrence H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl, aralkyl, ω-amino alkyl, ω-hydroxy alkyl, or ω-hydroxy alkenyl, each of which can be optionally substituted; 
 each of R′ and R″ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, ω-amino alkyl, ω-hydroxy alkyl, ω-hydroxy alkenyl, or ω-hydroxy alkynyl, each of which can be optionally substituted; and 
 each of m, n, p, q, r, and s is independently for each occurrence 0-10. 
 
     
     
         2 . The monomer of  claim 1 , wherein R 11  is a protecting group and R 12  is a reactive phosphorous group or solid support. 
     
     
         3 . The monomer of  claim 1 , wherein R 11  is a reactive phosphorous group or solid support and R 12  is a protecting group. 
     
     
         4 . The monomer of  claim 1 , wherein the reactive phosphorus group is selected from the group consisting of phosphoramidite, H-phosphonate, alkyl-phosphonate, and phosphate triester. 
     
     
         5 . The monomer of  claim 1 , wherein the protecting group is a hydroxyl protecting group selected from the group consisting of acetyl, benzyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, trityl, monomethoxytrityl, and dimethoxytrityl. 
     
     
         6 . An oligonucleotide comprising at least one monomer of  claim 1 . 
     
     
         7 . An oligonucleotide comprising at least one monomer of formula (IV′): 
       
         
           
           
               
               
           
         
       
       or isomers thereof, 
       wherein:
 each B is independently H or a nucleobase; 
 each of R 1 , R 2 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , and R 9  is independently for each occurrence H, halo, OR 13 , N(R′)(R″), alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, ω-amino alkyl, ω-hydroxy alkyl, ω-hydroxy alkenyl, or ω-hydroxy alkynyl, each of which can be optionally substituted; 
 R 11  and R 12  are independently for each occurrence H, 
 
       
         
           
           
               
               
           
         
       
       nucleoside, oligonucleotide, 
       
         
           
           
               
               
           
         
       
       —O-oligonucleotide, —S-oligonucleotide, —S—S-oligonucleotide, —N(R′)—C(Z 6 )-oligonucleotide, —C( Z   6 )—N(R′)-oligonucleotide, —N(R′)—C(Z 6 )Z 6 -oligonucleotide, —Z 6 C(Z 6 )—N(R′)-oligonucleotide, N(R′)C(Z 6 )N(R′)-oligonucleotide, 
       
         
           
           
               
               
           
         
         R 13  is independently for each occurrence H, alkyl, alkenyl, alkynyl, cycloalkyl, heterocyclyl, aryl, heteroaryl, heteroaryl, aralkyl, ω-amino alkyl, ω-hydroxy alkyl, or ω-hydroxy alkenyl, each of which can be optionally substituted; 
         R 14  is independently for each occurrence H, halo, OR 12 , N(R′)(R″), alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, ω-amino alkyl, ω-hydroxy alkyl, or ω-hydroxy alkenyl, each of which can be optionally substituted; 
         X 3 , X 4 , X 5 , and Z 3  are each independently for each occurrence H, O − , OM, OR 13 , S − , SR 13 , SM, N(R′)(R″), B(R 13 ) 3 , BH 3   − , or Se; 
         Y 3 , Y 4 , Y 5 , and Z 6  are each independently for each occurrence O or S; 
         Z 4  is independently for each occurrence O, S, CH 2 , or NR′; 
         each of R′ and R″ is independently for each occurrence H, alkyl, alkenyl, alkynyl, aryl, heteroaryl, cyclyl, heterocyclyl, ω-amino alkyl, ω-hydroxy alkyl, ω-hydroxy alkenyl, or ω-hydroxy alkynyl, each of which can be optionally substituted; 
         each of m, n, p, q, r, and s is independently for each occurrence 0-10; and 
         t is 0-2. 
       
     
     
         8 . The oligonucleotide of  claim 7 , wherein at least one of R 11  or R 12  is 
       
         
           
           
               
               
           
         
       
     
     
         9 . The oligonucleotide of  claim 7 , wherein the monomer is at the 5′-end terminal position of the oligonucleotide. 
     
     
         10 . The oligonucleotide of  claim 7 , wherein the monomer is at the 3′-end terminal position of the oligonucleotide. 
     
     
         11 . The oligonucleotide of  claim 7 , wherein the monomer is at an internal position of the oligonucleotide. 
     
     
         12 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises at least one non-phosphodiester internucleoside linkage. 
     
     
         13 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises at least one non-phosphodiester internucleoside linkage selected from the group consisting of phosphorothioate, phosphorodithioate, H-phosphonate, alkyl-phosphonate, phosphoramidate internucleoside linkages, and any combinations thereof. 
     
     
         14 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises at least one nucleobase modification. 
     
     
         15 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises at least one sugar modification. 
     
     
         16 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises at least one ligand conjugate. 
     
     
         17 . The oligonucleotide of  claim 7 , wherein the oligonucleotide is a double-stranded oligonucleotide comprising a first strand and a second strand. 
     
     
         18 . The oligonucleotide of  claim 17 , wherein the double-stranded oligonucleotide is a double-stranded siRNA. 
     
     
         19 . The oligonucleotide of  claim 7 , wherein the oligonucleotide is a single-stranded oligonucleotide. 
     
     
         20 . The oligonucleotide of  claim 19 , wherein the single-stranded oligonucleotide is a single-stranded siRNA. 
     
     
         21 . The oligonucleotide of  claim 7 , wherein the oligonucleotide is a hairpin oligonucleotide. 
     
     
         22 . The oligonucleotide of  claim 7 , wherein the oligonucleotide is an antisense oligonucleotide, an antagomir, a microRNA, a pre-microRNA, an antimir, a supermir, a ribozyme, a U1 adaptor, RNA activator, RNAi agent, a decoy oligonucleotide, a triplex forming oligonucleotide, or an aptamer. 
     
     
         23 . The oligonucleotide of  claim 7 , wherein the oligonucleotide comprises:
 1-20 first-type regions, each first-type region independently comprising 1-20 contiguous nucleosides wherein each nucleoside of each first-type region comprises a first-type modification;   0-20 second-type regions, each second-type region independently comprising 1-20 contiguous nucleosides wherein each nucleoside of each second-type region comprises a second-type modification; and   0-20 third-type regions, each third-type region independently comprising 1-20 contiguous nucleosides wherein each nucleoside of each third-type region comprises a third-type modification,   wherein the first-type modification, the second-type modification, and the third-type modification are each independently selected from the group consisting of 2′-F, 2′-OCH 3 , 2′-O(CH 2 ) 2 OCH 3 , BNA, F-HNA, 2′-H and 2′-OH.