Oligonucleotides containing 2'-0-modified purines

Abstract

Novel 2′-O-alkyl guanosine compounds are provided. In accordance with preferred embodiments compounds having the structure: wherein X is R 1 —(R 2 ) n ; R 1 is C 3 -C 20 alkyl, C 4 -C 20 alkenyl or C 2 -C 20 alkynyl; R 2 is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides; and n is an integer from 0 to about 6, are provided.

What is claimed is:  
     
         1 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 3 -C 20  alkyl, C 4 -C 20  alkenyl or C 2 -C 20  alkynyl;  
 R 2  is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, N-phthalimido, imidazole, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetiic properties of oligonucleotides; and  
 n is an integer from 0 to about 6.  
 
     
     
         2 . The compound of  claim 1  wherein R 1  is C 4 -C 20  alkyl.  
     
     
         3 . The compound of  claim 1  wherein R 1  is C 5 -C 20  alkyl.  
     
     
         4 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 3 -C 20  alkyl;  
 R 2  is NH 2 , imidazole, or N-phthalimido;  
 Y is a hydroxyl blocking group;  
 Z is phosphate or an activated phosphate group;  
 Q 1  and Q 2  independently are H or a guanosine blocking group; and  
 n is an integer from 0 to about 6.  
 
     
     
         5 . The compound of  claim 4  wherein: 
 Y is trityl, methoxytrityl, dimethoxytrityl or trimethoxytrityl.  
 
     
     
         6 . The compound of  claim 4  wherein: 
 Z is β-cyanoethyl-N,N-isopropylphosphoramidate.  
 
     
     
         7 . A compound having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 3 -C 20  alkyl, C 4 -C 20  alkenyl or C 2 -C 20  alkynyl;  
 R 2  is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides; and  
 n is an integer from 0 to about 6.  
 
     
     
         8 . The compound 2′-O-propylguanosine, 2′-O-pentylguanosine, 2′-O-nonylguanosine, 2′-O-octadecylguanosine, 2′-O-(N-phthalimido)-pentylguanosine, or 2′-O-(imidazol-1-yl)butylguanosine.  
     
     
         9 . An oligomer comprising at least one subunit having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 3 -C 20  alkyl, C 4 -C 20  alkenyl, or C 2 -C 20  alkynyl;  
 R 2  is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;  
 T 3  and T 5  independently are OH or a further subunit of said oligomer that is joined to said structure; and  
 n is an integer from 0 to about 6.  
 
     
     
         10 . An oligomer comprising at least one subunit having the structure:  
       
         
           
           
               
               
           
         
         wherein X is R 1 —(R 2 ) n ;  
         R 1  is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl;  
         R 2  is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, or a group that enhances the pharmacokinetic properties of oligonucleotides;  
         T 3  and T 5  independently are OH or a further subunit of said oligomer that is joined to said structure; and  
         n is an integer from 0 to about 6.  
       
     
     
         11 . A method of modulating the synthesis of a protein comprising specifically hybridizing with mRNA coding for said protein an oligomer comprising at least one subunit having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 3 -C 20  alkyl, C 4 -C 20  alkenyl, or C 2 -C 20  alkynyl;  
 R2 is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, and a group that enhances the pharmacokinetic properties of oligonucleotides;  
 T 3  and T 5  independently are OH or a further nucleotide or nucleoside of said oligonucleotide or oligonucleoside that is joined to said structure; and  
 n is an integer from 0 to about 6.  
 
     
     
         12 . The method of  claim 11  wherein said oligonucleotide is in a pharmaceutically acceptable carrier.  
     
     
         13 . A method of modulating the synthesis of a protein comprising specifically hybridizing with mgNA coding for said protein an oligomer comprising at least one subunit having the structure:  
       
         
           
           
               
               
           
         
       
       wherein X is R 1 —(R 2 ) n ; 
 R 1  is C 1 -C 20  alkyl, C 2 -C 20  alkenyl, or C 2 -C 20  alkynyl;  
 R 2  is halogen, hydroxyl, thiol, keto, carboxyl, nitro, nitroso, nitrile, trifluoromethyl, trifluoromethoxy, O-alkyl, S-alkyl, NH-alkyl, N-dialkyl, O-aryl, S-aryl, NH-aryl, O-aralkyl, S-aralkyl, NH-aralkyl, amino, imidazole, N-phthalimido, azido, hydrazino, hydroxylamino, isocyanato, sulfoxide, sulfone, sulfide, disulfide, silyl, aryl, heterocycle, carbocycle, intercalator, reporter molecule, conjugate, polyamine, polyamide, polyalkylene glycol, polyether, a group that enhances the pharmacodynamic properties of oligonucleotides, and a group that enhances the pharmacokinetic properties of oligonucleotides;  
 T 3  and T 5  independently are OH or a further nucleotide or nucleoside of said oligonucleotide or oligonucleoside that is joined to said structure; and  
 n is an integer from 0 to about 6.  
 
     
     
         14 . The method of claim  15  wherein said oligonucleotide is in a pharmaceutically acceptable carrier.